An Industry Perspective

Transcription

1 AIPPI World IP Congress 2014 Workshop Pharma 2 Biosimilar pharmaceutical products An Industry Perspective September 16, 2014 Masahisa Yamaguchi, PhD Department Manager Intellectual Property Dept. Chugai Pharmaceutical Co., Ltd.

2 About Chugai Pharmaceutical Co., Ltd. Head Office: Tokyo, Japan Revenue: \423.7 billion (Dec. 31, 2013) Number of Employees: 6,872 (Dec. 31, 2013) Principal Shareholder: Roche Holding Ltd (61.56%) PEGASYS TAMIFLU SIGMART COPEGUS CELLCEPT etc. Renal Diseases 12.8% Others 17.4% Oncology 45.3% AVASTIN HERCEPTIN RITUXAN XELODA NEUTROGIN /GRANOCYTE TARCEVA etc. EPOGIN MIRCERA Bone&Joint Diseases OXAROL RENAGEL etc. 24.5% ACTEMRA /RoACTEMRA EDIROL ALFAROL etc. Red:Bio-products 1

3 Table of Content 1. Scientific Aspects of Biologics and Biosimilars 2. Regulations and Guidelines for Biosimilars 3. Development Status of Biosimilars 2

4 Table of Content 1. Scientific Aspects of Biologics and Biosimilars 2. Regulations and Guidelines for Biosimilars 3. Development Status of Biosimilars 3

5 Types of Pharmaceuticals Molecular Weight (180) Aspirin (447) Pravastatin (1,202) Ciclosporin (5,807) Insulin (30,000) Epoetin beta (150,000) Antibody 100 1,000 10, ,000 Manufacturing Characteristics Chemical Products Chemical synthesis Relatively simple manufacturing process Small, simple, low molecular weight Rigid and stable structure Characterization Easy to characterise and purify Biological Products Biological synthesis using human DNA, bacterial or animal cell lines Complex manufacturing process Large, heterogeneous, high molecular weight Flexible and labile structure Difficult to characterise and purify Examples Conventional drugs Protein product, Antibody product 4

6 Size, Structure & Complexity Size Small molecule drug Aspirin 21 atoms Large molecule drug Human growth hormone (hgh) ~ 3,000 atoms Large biological drug IgG antibody ~ 25,000 atoms Complexity Bike ~ 20 lbs Car ~ 3,000 lbs Business jet ~ 25,000 lbs (without fuel) 5

7 Manufacturing Process for Biologics Master cell line Each stage of the complex manufacturing process confers unique properties on the resulting biologic product: The process is the product 6

8 Small Molecule Drugs and Biological Drugs Small molecule drug Homogeneous Single molecule Biological drug Heterogeneous Mix. of various molecules Active Active ingredient Variant (active) Variant (inactive) Decomposed Impurity (host) Impurity (process) Inactive Even if a biosimilar developer uses the same DNA sequence as the innovator, the final biosimilar drug will differ from the reference drug: clinical outcomes of a biosimilar drug also could differ 7

9 Biosimilar product Similarity Reference product Similarity in Biologics Factors Affecting Similarity Quality Characteristics Physicochemical Biological Surrogate maker Pharmacokinetics Pharmacodynamics Manufacturing Process Master cell Culture conditions Purification Formulation Experience/Know-how Manufacturing Analysis Biological Clinical Clinical Outcomes Efficacy Safety Immunogenicity Biosimilar developers can use only a part of Quality Characteristics : intensive and detailed evaluation and comparison should be required 8

10 Heterogeneity of EPO Products 9

11 Difference in Reditux and Rituxan Intended copy Reditux (Dr. Reddy) April 30, Same amino acid sequence Host cell protein content much higher Content of aggregates not comparable Glycosylation not comparable Effector function not comparable 280 nm Reditux Different manufacturer means: Different drug Different clinical profile? Rituxan Ref Mat Time (minutes) Comparison by Cation Exchange Chromatography R. Harris (2008) presentation at Biogenerics 2008 Data source: Genentech (Matt Field, Susan Gruerman) 10

12 Scientific Aspects of Biological Drugs Small Molecule Drugs: Possible to produce the exact copy of a reference drug Biological Drugs: Impossible to produce the exact copy of a reference drug Complexity of the structure and 3D-conformation Heterogeneous mixtures of protein molecules with different physical, chemical and biological properties Limited scientific approaches to assess chemical and biological characteristics Variations in the manufacturing process It is necessary for the market approval of a biosimilar to conduct clinical tests for efficacy and safety in addition to quality characteristics 11

13 Table of Content 1. Scientific Aspects of Biologics and Biosimilars 2. Regulations and Guidelines for Biosimilars 3. Development Status of Biosimilars 12

14 Guidelines for Biosimilars JP Guideline for ensuring quality, safety and efficacy of biosimilars ( ) US EP Draft: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (2012) Draft: Quality considerations in Demonstrating Biosimilarity to a Reference Protein Product (2012) Draft: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (2012) Draft: Clinical Pharmacology Data to support a Demonstration of Biosimilarity to a reference Product (2014) [General] Similar biological medicinal products ( ) [Quality issues] Similar biological medicinal products containing biotechnologyderived proteins as active substance: quality issues (2006.6) [Non-clinical, clinical issues] Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (2006.6) [Product class specific guidelines] insulin (2006.7) revised (2012), somatropin (2006.7), G-CSG (2006.7), IFN-alpha (2009.4), LMW-heparins ( ), EPO (2006.7) revised (2010.9), Mab ( ), IFN-beta, FSH (2013.9) 13

15 Major Features of JP/EU/US Guidelines JP EP US Framework Single guideline covering all biotech-based drugs An overarching GL + GLs for quality and non-clinical and clinical issues + Product class specific GLs Draft: Scientific Considerations, Quality Considerations, Clinical Pharmacology Data Basic concept Evaluation by comparability studies on quality and PK/PD profiles, together with clinical data complementing the data (case-by-case and stepby-step approach) Proof of similarity in combination of quality, non-clinical and clinical study data based on comparative studies (case-by-case) FDA recommends a stepwise approach to assess the demonstration of biosimilarity using a totality-of-the-evidence approach. PV Plans for post-marketing surveillance study and risk management required at submission of application Naming Different nonproprietary and brand names required distinguishable from the reference drug and other biosimilar drugs same nonproprietary name as the reference drug No mention 14

16 Image of Data Requirements in Japan Not available for biosimilar developer Comparability to the comparator Comparability data required by ICH Q5E Case-by-case Step-by-step Depends on data until then Process Quality characeristics of biosimilar (full data) Manufa cturing Quality Nonclinical PK/PD Efficacy Safety Postmarketing Comparative Data Independent Data Clinical 15

17 Biosimilar Naming WHO A different nonproprietary name from the reference drug INN of the reference product + a unique suffix (called a biological qualifier ) EP The same nonproprietary name as the reference drug Australia A different nonproprietary name from the reference drug ABN of the reference product + a biosimilar identifier Japan A different nonproprietary name from the reference drug JAN of the reference product + JAN biosimilar + number Reference Product: Filgrastim (recombinant) First Biosimilar by Mochida : Filgrastim (recombinant) [filgrastim biosimilar 1] Second Biosimilar by NK: Filgrastim (recombinant) [filgrastim biosimilar 2] For Trade name: JAN of the reference product + BS + Dosage form + company name Reference Product: Neupogen First Biosimilar by Mochida: Filgrastim BS injection [Mochida] Second Biosimilar by NK: Filgrastim BS injection [NK] 16

18 Debates on Biosimilar Naming Should biosimilars go by a different nonproprietary name? Pros: Biologicals are scientifically different than traditional chemical drugs No two biological products made from different cell lines and/or using different manufacturing processes are ever identical to the reference product they aim to replicate Knowing specifically which product, and by which manufacturer it was produced that a patient received is essential to keeping medicines and patients safe Cons: The lack of global consistency for naming of biosimilars will result in a loss of scientific basis for naming, confusion and uncertainty for practitioners and patients and inappropriately delayed access to affordable biologicals The current INN scheme works well within the EU and that the creation of new names/identifiers will cause confusion and constitutes a safety issue It is not problematic to identify the biological products, which are subject to adverse reaction reports 17

19 Table of Content 1. Scientific Aspects of Biologics and Biosimilars 2. Regulations and Guidelines for Biosimilars 3. Development Status of Biosimilars 18

20 Development Status of Biosimilars Product Biosimilar Company Reference EP US JP Somatropin /hgh Epoetin alfa Epoetin zeta Epoetin theta Omnitrope Somatropin BS Sandoz (Novartis) Genotropin (Pfizer) Apr May 2007* Jun Valtropin BioPartners (Bioton) Humatrope (EliLilly) Apr Apr. 2007* - Abseamed Medice Arzneimittel Eprex/Erypo (J&J) Aug Binocrit Sandoz (Novartis) Eprex/Erypo (J&J) Aug Epoetin alfa Hexal Hexal Eprex/Erypo (J&J) Aug Retacrit Hospira Eprex/Erypo (J&J) Dec Silapo Stada Eprex/Erypo (J&J) Dec Eporatio Ratiopharm Eprex/Erypo (J&J) Oct Biopoin Teva/CT Arzneimittel Eprex/Erypo (J&J) Oct Epoetin kappa Epoetin alfa BS JCR/Kissei Espo (Kyowa-Kirin) - - Jan Filgrastim Biograstim CT Arzneimittel Neupogen (Amgen) Sep Filgrastim ratiopharm Ratiograstim Ratiopharm Neupogen (Amgen) Sep Tevagrastim Teva Neupogen (Amgen) Sep Aug. 2012** - Zarzio Sandoz (Novartis) Neupogen (Amgen) Feb Filgrastim Hexal Hexal Neupogen (Amgen) Feb Nivestim Hospira Neupogen (Amgen) Jun Filgrastim BS Fuji/Mochida Gran (Kyowa-Kirin) - - Nov Filgrastim BS Teva/NihonKayaku Gran (Kyowa-Kirin) - - Feb * Based on FDCA 505(b)(2), not as a Biosimilar **Based on BLA, not as a Biosimilar (As of Feb. 2013) 19

21 Development cost Current Situation of Biosimilars Small compound drugs: over 800M USD, 8-10 years, patients Generics: 2-3M USD, 2-3 years, patients Biosimilars: M USD, 6-8 years, patients Price 10-35% reduction in price compared to reference product in EP and JP Penetration EU market penetration (volume) of hgh, EPO, G-CSF is 10-30% JP market penetration (volume) is slower than EP situation Substitution Authorities in EP and JP are against biosimilar substitution 20

22 Competitive Powers of Biosimilars Reference Product Price Price Reduction = Price competitiveness of Generics Price competitiveness of Biosimilars Biosimilar Price Additional Cost for Biosimilars Production Cost Pre-clinical Clinical Post-marketing Surveillance Generic Price The price difference between the reference biological product and biosimilars are small and cannot be an effective driver for penetration 21

23 Antibodies: Still a Market Growth Driver (million USD) 350, , ,000 Other biotech product Bioengineered vaccine Monoclonal antibody Recombinant product 200, , ,000 50,000 0 As of Source: Evaluate Pharma 22

24 Biosimilar Monoclonal Antibody Clinical Trial Registration Approved Infliximab Pfizer, Samsung, Reliance, Sanofi/Nichiiko Celltrion in US (2014), Hospira/Celltrion in EP and KR (2013), Nippon Kayaku in JP (2014), Etanercept Sandoz, Samsung, LG Lifesciences, Reliance Hanwha in KR Cipra in IN, Probopmed in MX, Shanghai CPG in CN and others. Adalimumab Pfizer, Fujifilm/Kirin, Boehringer Ingelheim Rituximab Pfizer, Sandoz, Boehringer Ingelheim, Lanbaxy, Reliance Shanghai CPG in CN Dr Reddys (IC) in IN, Probiomed in MX (2013), Biocad in RU (2014) Trastuzumab Pfizer, Reliance, Nippon Kayaku, Probiomed, Hanwha Celltrion in KR, Shanghai CPG in CN Mylan in IN (2014) Bevacizumab Pfizer, Reliance, Amgen/Actavis, Boehringer Ingelheim 23

25 Unsuccessful Development of Biosimilar Antibody Teva halts phase III biosimilar rituximab trial (GaBI Online, 12/10/2012) Israel generics giant Teva Pharmaceutical Industries (Teva) has suspended its phase III trial of its biosimilar version (TL011) of Roche s Rituxan/MabThera (rituximab). [Collaborating with Lonza] Samsung halts biosimilar rituximab development (GaBI Online, 19/10/2012) South Korean electronics giant Samsung has halted clinical development for the biosimilar version (SAIT101) of Roche s Rituxan/MabThera (rituximab). [Collaborating with Biogen Idec] Celltrion Drops Late-Stage Trial of Roche Rituxan Drug Copy (Bloomberg, 18/04/2013) Celltrion Inc. dropped a late-stage trial of a biosimilar version of Roche Holding AG best-selling Rituxan drug, potentially benefiting competitors such as Boehringer Ingelheim GmbH and Novartis AG. 24

26 Summary Biological products are complex and difficult to produce exactly the same product unlike small molecule generic drugs Generally, intensive quality data and non-clinical and clinical study data based on comparative studies are necessary for biosimilar market approvals Current evidence suggests that biosimilars show a relatively slow market penetration Biosimilar monoclonal antibodies are the next target and many companies including innovator companies and companies from the outside industry are trying to enter the market Successful development of biosimilar monoclonal antibodies might require strong technical and financial power 25

27 Thank you for your attention!