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.
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%)
Oncology 45.3% Bone&Joint Diseases 24.5% Renal Diseases 12.8% Others
17.4% AVASTINRITUXAN®® HERCEPTIN XELODA® ®
NEUTROGIN®/GRANOCYTE®
TARCEVA® etc.
EPOGIN® MIRCERA®
OXAROL® RENAGEL®
etc. ACTEMRA ® /RoACTEMRA®
EDIROL® ALFAROL® etc.
PEGASYS® TAMIFLU®
SIGMART® COPEGUS®
1. Scientific Aspects of Biologics and Biosimilars
2. Regulations and Guidelines for Biosimilars
3. Development Status of Biosimilars
1. Scientific Aspects of Biologics and Biosimilars
2. Regulations and Guidelines for Biosimilars
3. Development Status of Biosimilars
Types of Pharmaceuticals
Molecular Weight 1,000 100 10,000 100,000 （180）Aspirin Pravastatin （447） Ciclosporin （1,202） （Insulin 5,807） Epoetin beta （30,000） （Antibody 150,000）
Chemical Products Biological Products
Manufacturing • Chemical synthesis • Relatively simple
manufacturing process
• Biological synthesis using human DNA, bacterial or animal cell lines
• Complex manufacturing process Characteristics • Small, simple, low
molecular weight • Rigid and stable
structure
• Large, heterogeneous, high molecular weight
• Flexible and labile structure Characterization • Easy to characterise
and purify
• Difficult to characterise and purify Examples • Conventional drugs • Protein product, Antibody product
Size, Structure & Complexity
Si ze C omp le xi ty Large molecule drug Human growth hormone (hGH) ~ 3,000 atoms Car ~ 3,000 lbs Large biological drug IgG antibody ~ 25,000 atoms Business jet ~ 25,000 lbs (without fuel) Small molecule drug Bike ~ 20 lbs Aspirin 21 atomsManufacturing 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
Small Molecule Drugs and Biological Drugs
Small molecule drug Biological drug
Active ingredient Variant (active) Variant (inactive) Impurity (host) Decomposed Impurity (process) Homogeneous Single molecule Heterogeneous
Mix. of various molecules
Active
Inactive
Even if a biosimilar developer uses the same DNA sequence as the
innovator, the final biosimilar drug will differ from the reference drug:
Similarity in Biologics
Efficacy SafetyReference
product
Biosimilar
product
SimilarityBiosimilar developers can use only a part of “Quality Characteristics”:
intensive and detailed evaluation and comparison should be required
Immunogenicity Quality Characteristics Physicochemical Biological Surrogate maker Pharmacokinetics Pharmacodynamics Manufacturing Process Master cell Culture conditions Purification Formulation Experience/Know-how Manufacturing Analysis Biological Clinical
Difference in Reditux and Rituxan
0 40 80 120 160 0 10 20 30 40 50 A U F S @ 280 nm Time (minutes)Rituxan Ref Mat Reditux
Same amino acid sequence
Host cell protein content much higher Content of aggregates not comparable Glycosylation not comparable
Effector function not comparable
Different manufacturer means: • Different drug
• Different clinical profile?
Comparison by Cation Exchange Chromatography
R. Harris (2008) presentation at „Biogenerics 2008“ Data source: Genentech (Matt Field, Susan Gruerman)
Reditux (Dr. Reddy) April 30, 2007 Intended copy
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
1. Scientific Aspects of Biologics and Biosimilars
2. Regulations and Guidelines for Biosimilars
3. Development Status of Biosimilars
Table of Content
Guidelines for Biosimilars
JP
• Guideline for ensuring quality, safety and efficacy of biosimilars (2009.3.4)US
• 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)
EP
• [General] Similar biological medicinal products (2005.10)
• [Quality issues] Similar biological medicinal products containing biotechnology-derived 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 (2009.10), EPO
Major Features of JP/EU/US Guidelines
JP EP US
Frame-work Single all biotech-based drugs guideline covering An for quality and non-clinical overarching GL + GLs 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 step-by-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
Image of Data Requirements in Japan
Not available for biosimilar
developer
Quality
Non-clinical PK/PD Efficacy Safety Post- marketing Clinical Quality characeristics of biosimilar (full data) Comparability to the comparator Comparability data required by ICH Q5E Case-by-case Step-by-step
Depends on data until then
Process
Manufa cturing
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]
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
1. Scientific Aspects of Biologics and Biosimilars
2. Regulations and Guidelines for Biosimilars
3. Development Status of Biosimilars
Development Status of Biosimilars
Product Biosimilar Company Reference EP US JP
Somatropin /hGH
Omnitrope
Somatropin BS Sandoz (Novartis) Genotropin (Pfizer) Apr. 2006 May 2007* Jun. 2009 Valtropin BioPartners (Bioton) Humatrope (EliLilly) Apr. 2006 Apr. 2007* -
Epoetin alfa
Abseamed Medice Arzneimittel Eprex/Erypo (J&J) Aug. 2007 - - Binocrit Sandoz (Novartis) Eprex/Erypo (J&J) Aug. 2007 - - Epoetin alfa Hexal Hexal Eprex/Erypo (J&J) Aug. 2007 - -
Epoetin zeta Retacrit Hospira Eprex/Erypo (J&J) Dec. 2007 - -
Silapo Stada Eprex/Erypo (J&J) Dec. 2007 - -
Epoetin theta Eporatio Ratiopharm Eprex/Erypo (J&J) Oct. 2009 - - Biopoin Teva/CT Arzneimittel Eprex/Erypo (J&J) Oct. 2009 - - Epoetin kappa Epoetin alfa BS JCR/Kissei Espo (Kyowa-Kirin) - - Jan. 2010
Filgrastim
Biograstim CT Arzneimittel Neupogen (Amgen) Sep. 2008 - -
Filgrastim ratiopharm
Ratiograstim Ratiopharm Neupogen (Amgen) Sep. 2008 - -
Tevagrastim Teva Neupogen (Amgen) Sep. 2008 Aug. 2012** -
Zarzio Sandoz (Novartis) Neupogen (Amgen) Feb. 2009 - -
Filgrastim Hexal Hexal Neupogen (Amgen) Feb. 2009 - -
Nivestim Hospira Neupogen (Amgen) Jun. 2010 - -
Filgrastim BS Fuji/Mochida Gran (Kyowa-Kirin) - - Nov. 2012
Current Situation of Biosimilars
Development cost
• Small compound drugs: over 800M USD, 8-10 years, 500-1000 patients
• Generics: 2-3M USD, 2-3 years, 20-50 patients
• Biosimilars: 75-250M USD, 6-8 years, 100-500 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
Competitive Powers of Biosimilars
Additional Cost for Biosimilars • Production Cost • Pre-clinical • Clinical • Post-marketing Surveillance Biosimilar Price Price competitiveness of Biosimilars
Reference Product Price
Generic Price Price competitiveness of Generics Price Reduction
=
The price difference between the reference biological product and
biosimilars are small and cannot be an effective driver for penetration
0 50,000 100,000 150,000 200,000 250,000 300,000 350,000 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Other biotech product
Bioengineered vaccine Monoclonal antibody Recombinant product
Antibodies: Still a Market Growth Driver
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 MX, Shanghai CPG IN, Probopmed 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,
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.
