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Ropes & Gray, LLP The Evolving Biosimilars Landscape: Is the US Ready for the Opportunities and Challenges?
New York Pharma Forum Robert Rouse, Senior Principal Paul Villa, Senior Principal
May 13, 2015 Content
• The Opportunity
• The European Experience
• The US Challenges
• Conclusions
The Evolving Biosimilar Landscape: Opportunities & Challenges 2 May 13, 2015 Pharmaceutical spending continues upward with an
estimated 3-6% global CAGR through 2020
Major Markets Spending and Growth on Pharmaceuticals 2010-2020 China
1000 30% Opportunity
900 Japan 25% 800 EU5
700 20%
600 15% USA 500 10% USA growth 400
300 5% EU5 growth
SPENDING US$BN US$BN SPENDING 200
0% US$% CONST GROWTH Japan growth 100
0 -5% China growth 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020
Forecast USA, EU5, Japan, China constant dollar growth
Source: IMS Market Prognosis Apr 2015; (*) at ex-manufacturer price levels, not including rebates and discounts
The Evolving Biosimilar Landscape: Opportunities & Challenges 3 May 13, 2015 Biologics growth continues to outstrip total pharma, showing a steep increase on 2013
Such a trend is putting additional financial pressure on healthcare budgets
Global Market Trends Biologics – 2014 Share of sales
Sales and Growth Opportunity 250 12% 21% 51%
10% 200
6%
8% 10% 150 12% 6% EU5 Japan Pharmerging ROW US 100
4% Growth, LCUS$ Sales, US$ Sales, billions 50 Biologics – Share of 5 yr growth 2% 15%
0 0% 55% 6% 2008 2009 2010 2011 2012 2013 2014
Biologics Sales Biologics growth 14% Small molecule growth 11%
Source: MIDAS IMS Health, MAT Q3 2014, Rx; Brazil and Mexico Non Retail Sales are included; Share of growth in LC$
The Evolving Biosimilar Landscape: Opportunities & Challenges 4 May 13, 2015 Biologics increasingly feature as key therapies
Payers see their costs increasing
Global top 10 products 2009-14 Opportunity 2009 2010 2011 2012 2013 2014
1 LIPITOR LIPITOR LIPITOR SERETIDE HUMIRA HUMIRA
2 PLAVIX PLAVIX PLAVIX CRESTOR SERETIDE LANTUS
3 NEXIUM SERETIDE SERETIDE HUMIRA CRESTOR ABILIFY
4 SERETIDE NEXIUM NEXIUM NEXIUM ENBREL SERETIDE
5 SEROQUEL SEROQUEL CRESTOR LIPITOR NEXIUM ENBREL
6 ENBREL CRESTOR SEROQUEL ENBREL ABILIFY CRESTOR
7 REMICADE ENBREL HUMIRA REMICADE REMICADE REMICADE
8 ZYPREXA REMICADE ENBREL PLAVIX LANTUS NEXIUM
9 CRESTOR HUMIRA REMICADE ABILIFY CYMBALTA SOVALDI
10 SINGULAIR ZYPREXA ZYPREXA LANTUS MABTHERA MABTHERA
Small molecule products Biologic products
Source: IMS Health, MIDAS, MAT Sep 2014
The Evolving Biosimilar Landscape: Opportunities & Challenges 5 May 13, 2015
It’s the loss of exclusivity that drives biosimilar interest
All these products will lose patent protection by 2020 (except Enbrel in the US)
Global Sales (MAT 06/2014), US$ billion EU expiry date US expiry date Opportunity
10.8 Adalimumab (Humira) 2018 2016
9.2 Insulin Glargine (Lantus) 2015 2016
8.3 Etanercept (Enbrel) 2015 2028 (extended)
7.9 Infliximab (Remicade) 2015 2018
6.4 Rituximab (Mabthera) Expired 2018
6.3 Insulin Aspart (Novomix, Novorapid) Expired Expired
5.9 Bevacizumab (Avastin) 2019 2019
5.5 Interferon Beta-1A (Avonex, Rebif) 2015 2016 Expired 2019 5.3 Total Trastuzumab (Herceptin) 4.6 ~ US$ 79 Glatiramer Acetate (Copaxone) 2017 2015 billion 4.5 Pegfilgrastim (Neulasta) 2015 2015
4.5 Ranibizumab (Lucentis) 2016 2016
0 5 10 15 Not considered existing biosimilars such as Epoetin Alfa expired in EU, but still patent protected in the US
Source: IMS MIDAS, 06/2014, Rx bound, IMS Patent focus
The Evolving Biosimilar Landscape: Opportunities & Challenges 6 May 13, 2015 Globally, an upside potential up of $25bn in 2020
presumes a developed US market
Biosimilars market evolution, 2011 - 2020
2015 2020 Share of biologics Opportunity $1.9bn – $2.6bn $11bn – $25bn market - 2020 30 • Slow uptake in the US due to • Key upside drivers represented 25 new legislation enabling by the US biosimilar market: innovators to delay the US holding ~54% market value 25 10% approval process of new by 2020 biosimilars 20 • Europe to hold ~25% market • Uptake in Europe accelerates value by 2020, if US fails to 20 8% 15 due to more mature take off Europe increases in framework accounting for importance 35-41% market value by 10 2015 11 4% • Emerging countries (Asia
5 specifically) ramping up Biosimilar Biosimilar market size, $LCbn - 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Lower Bound Base Case Upper Bound
Source: IMS analysis on MIDAS data, Extrapolation of MIDAS data, Price cut set at 40-50%, uptake curves based on analogues and evidence from marketed biosimilars
The Evolving Biosimilar Landscape: Opportunities & Challenges 7 May 13, 2015 Content
• The Opportunity
• The European Experience
• The US Challenges
• Conclusions
The Evolving Biosimilar Landscape: Opportunities & Challenges 8 May 13, 2015 At the end of 2014, nine distinct biosimilar products were
being marketed in the European Union
Generic/ Decision Trade name Company Decision Common name date(s)
Somatropin Omnitrope® Sandoz 12-Apr-06 Approved Opportunity ® Binocrit Sandoz Epoetin alfa Epoetin alfa Hexal® Hexal 28-Aug-07 Approved Abseamed® Medice Retacrit® Hospira Epoetin zeta 18-Dec-07 Approved Silapo® Stada
Tevagrastim® Teva EU Experience EU Filgrastim Ratiograstim® Ratiopharm 18-Sep-08 Approved Biograstim ® CT Arzneimittel Zarzio® Sandoz Filgrastim 6-Feb-09 Approved Filgrastim Hexal® Hexal Filgrastim Nivestim® Hospira 10-Jun-10 Approved Filgrastim Grastofil® Apotex 18-Oct 13 Approved Inflectra® Celltrion Infliximab 10-Sep-13 Approved Remsima® Hospira Follitropin alpha Ovaleap® Teva 27-Sep-13 Approved
Eli Lilly/BI biosimilar insulin glargine of Sanofi “Lantus” product has received marketing authorization but cannot launch until expected 5/2015 patent expiry
Source: European Public Assessment Reports. Published on EMA Website
The Evolving Biosimilar Landscape: Opportunities & Challenges 9 May 13, 2015 Penetration of biosimilars across different therapy areas has been variable for a number of reasons
Stakeholder landscape – payer-driven vs. multiple influencers – and treatment cycle are the key determinants
Filgrastim uptake Somatropin uptake
2007-2013, yearly 2007-2013, yearly Opportunity
Commodity market Differentiated market
100% 100%
80% 80%
60% 60%
40% 40% EU Experience EU 20% 20%
0% 0%
% Uptake, DDD Uptake, % DDD Uptake, % 2007 2008 2009 2010 2011 2012 2013 T0 T1 T2 T3 T4 T5 T6
FRANCE GERMANY ITALY FRANCE GERMANY ITALY SPAIN UK SPAIN UK
Payer-driven market access (e.g. Tender, step- Complex stakeholder landscape with higher wise algorithms) physician influence
Price-driven competition Competition based on multiple marketing levers
Acute treatment and/or frequent cycling among Chronic treatment and/or long therapeutic therapies cycles
Source: IMS MIDAS year 2013. (*) Uptake is defined as penetration of accessible market. This includes reference and non reference prods
The Evolving Biosimilar Landscape: Opportunities & Challenges 10 May 13, 2015
What really drives biosimilars uptake?
Sets the market environment Best evidence Payer for other stakeholders learnings Environment Maximum biosimilar uptake could be achieved if a national single Opportunity
sourced tender for coverage of the
entire therapy area is implemented EU Experience EU Drivers? Price Clinical/Device Differential Innovation
Moving patients to the next Doesn't always correlate to standard of care biosimilar uptake Second generation products have in Actions taken by manufacturers in some cases had significant impact: specific markets are observed as - Sometimes by strategic pricing having an impact on biosimilar - Sometimes by recognized value or uptake and affecting the competitive improved outcomes environment Source : IMS Health insight
The Evolving Biosimilar Landscape: Opportunities & Challenges 11 May 13, 2015 To what extent has usage shifted to 2nd generation
products?
EPO: Uptake of 2nd Generation in the Total Market (% of treatment days 2013)
• For EPO’s, patent protected Opportunity 100% 96%
2nd generation products are
90% available 80% • Denmark has low uptake of 70% 63% 59% EPO biosimilars as the
60% market shifted to 2nd EU Experience EU 50% 45% generation 42% Successful originator 40% 31% strategy 30% 20% 17% • Differently in Italy and Poland, market remained on 10% first generation EPO 0% Originators are Poland Italy Spain Germany France UK Denmark successfully competing with pricing strategy
The Evolving Biosimilar Landscape: Opportunities & Challenges 12 May 13, 2015 Infliximab biosimilar has shown strong uptake in tender markets but much more moderated in others
Infliximab Monthly uptake Infliximab Monthly uptake Normalised uptake Cumulative uptake (last 3 months)* 80%
70% Dec’14-Feb’15 60% POLAND 46% 50% Tender markets NORWAY 36%
40% HUNGARY 20% Uptake, TD Uptake, 30% CROATIA 19%
20% CZECH 11%
10% FINLAND 9%
0%
ROMANIA 9%
T5 T0 T1 T2 T3 T4 T6 T7 T8 T9
T11 T12 T13 T14 T15 T16 T17 T10 SLOVAKIA 4%
CROATIA CZECH FINLAND IRELAND 3% HUNGARY IRELAND NORWAY POLAND ROMANIA SLOVAKIA
Will Infliximab biosimilar be used instead of the originator? Will it impact the usage of other anti-TNFs such as Humira and Enbrel? Will MABs be used more widely?
Source: IMS MIDAS monthly Feb 2015. Penetration calculated in treatment days (TD); *Bulgaria and Latvia excluded because only biosimilar manufacturers present; Hungary excluded as biosimilar penetration not captured from Nov 2014
The Evolving Biosimilar Landscape: Opportunities & Challenges 13 May 13, 2015 Content
• The Opportunity
• The European Experience
• The US Challenge
• Conclusions
The Evolving Biosimilar Landscape: Opportunities & Challenges 14 May 13, 2015 There are several key challenges for US biosimilar uptake
• Naming Regulatory • Extrapolation • Interchangeability
• The value drivers for biosimilars will differ widely across Customers customer groups– impossible to have a “one size fits all” strategy
• Innovator strategies Competition • Price benchmarking
• Given range in customers and customer needs, contracting Pricing/Contracting levels and approaches will also vary and must be targeted carefully
• Given the lack of government direction, various J-code Coding scenarios must be considered, each with different implications
The Evolving Biosimilar Landscape: Opportunities & Challenges 15 May 13, 2015 The regulatory pathway in the US is gaining more clarity
Potential Approval Pathways Biosimilars Filed/Approved
• Cenestin –(synthetic conjugated estrogen) • Fortical (salmon calcitonin recombinant) New Drug Application - 505(b)(2) • Omnitrope (human growth hormone recombinant) • Basaglar (insulin glargine)
Abbreviated New Drug Application - • Pergonal (menotropins) ANDA • Lovenox (enoxaparin)
Non-abbreviated Biologic License • Granix (tbo-filgrastim) Application (BLA) - 351(a)
Biologics Price Competition & Innovation Act (BPCI Act) of 2009 Signed in to law in 2010 as part of the Patient Protection Affordable Care Act (PPACA)
Abbreviated Biologic License • Zarxio (filgrastim –sndz) Application -351(k) • Remsima (infliximab)
The Evolving Biosimilar Landscape: Opportunities & Challenges 16 May 13, 2015 But, there are still are elements of the 351k pathway that will be clarified over time
Inter- Potential Approval Pathways Extrapolation Naming changeability
Same generic New Drug Application - 505(b)(2) name
Abbreviated New Drug Application - Same generic ANDA name
Non-abbreviated Biologic License Application (BLA) - 351(a)
Biologics Price Competition & Innovation Act (BPCI Act) of 2009 Signed in to law in 2010 as part of the Patient Protection Affordable Care Act (PPACA)
Abbreviated Biologic License Application -351(k)
The Evolving Biosimilar Landscape: Opportunities & Challenges 17 May 13, 2015 Without interchangeability, pharmacy benefit biosimilars
will be treated as lower cost brand options
Situation: The FDA approved enoxaparin with AB rating, allowing automatic pharmacy substitution Opportunity
Result: Cliff-like drop in sales of Lovenox, typical to introduction
of generic product
EU Experience EU
Situation: Omnitrope entered a mature HGH market without bioequivalent status Challenge US Result: Despite 30-40% cost reduction from reference product, market share lagged below 10% through 2010
Source: Health Affairs, 33, no.6 (2014):1048-1057.
The Evolving Biosimilar Landscape: Opportunities & Challenges 18 May 13, 2015 Payer management and the incentives they implement for
biosimilar use will be a key determinant of success
Payer Perceptions and Management of Biosimilars
Opportunity
Generic-like Another Brand
Payers incentivize Payers manage biosimilar utilization biosimilars in the same via restrictions and way they would Experience EU reimbursement manage a new branded agent
Payer Pressure US Challenge US
Economic challenges combined with significant spend on biologics will drive management towards a generic-like market
The Evolving Biosimilar Landscape: Opportunities & Challenges 19 May 13, 2015 However, establishing the US market will be a significant
challenge
Establishing clinical Competitive Patient incentives experience dynamics and risk
• EPOs and G-CSFs will have 6+ • Especially in autoimmune • As more competitors enter years experience on the diseases and cancer, patient markets, price competition Opportunity
European market before they perception and preference will inevitable launch in the US; physician play a strong role in acceptance • The right combination of product acceptance likely to be and uptake of biosimilars and company perception with generated rapidly • Payers could play a key role in effective contracting approaches • Biosimilars in areas with less or incentivising patients via co- will be crucial no clinical experience elsewhere pay rules but will only do so if
• Safety and immunogenicity Experience EU will find it much harder to fully convinced of safety and issues will be under ongoing establish efficacy scrutiny – a major problem for • Autoimmune may be especially • Companies could support any biosimilar product could have problematic due to a combination patient acceptance with patient spillover negative consequences of disease chronicity, few new assistance programs, DTC and e- for the whole market starts and little initial opportunity channels • Manufacturing capacity to for switch Challenge US address the high volumes of the US market and meet contract commitments essential Pioneer companies will need to Important to understand patient Crucial to have contracting invest in biosimilar market perception & levers to drive expertise and highly effective creating activities - and ensure acceptance as well as sequence negotiating skills on price but they are the main beneficiaries, of acceptance between also to maintain a high quality at a profitable level? stakeholders & relative influence reputation
The Evolving Biosimilar Landscape: Opportunities & Challenges 20 May 13, 2015 Originators will employ a range of defense approaches to
contain the impact of biosimilars
Potential Originator Defense Strategies
Moderate risk to originator High risk to originator
Opportunity
high Focus on brand value/patient File legal challenges
segments Consider new IP protected Consider splitting business offerings high value brand and a low Fight on price, if you are price alternative prepared to go to commodity
levels Experience EU
Low risk to originator Moderate risk to originator Focus on building brand value Fight on price even where and patient/prescriber loyalty discounts are low: ensure small price discounts do not Monitor market closely to let biosimilars gain significant Challenge US detect signs of movement to traction
one of the other scenarios
Biosimilar Price Incentives (discount) Incentives Price Biosimilar low
low high Willingness to Use Biosimilars (physician/patient acceptance)
The Evolving Biosimilar Landscape: Opportunities & Challenges 21 May 13, 2015 There is no consensus on the magnitude of potential
savings from biosimilars
Biosimilars are coming and it is critical to appropriately manage cost savings expectations, but estimates are wildly divergent
CBO projects $25 Billion Opportunity
in savings2 • CBO expects $25 billion reduced total expenditures on biologics ESI projects $250 million over the 2009-2018
in savings... period Experience EU
• Express Scripts projects • Over that 10-year period, the U.S. would save $250 such savings would equal billion between 2014 and roughly 0.5 percent 2024 if just the 11 likeliest biosimilars would enter the market1 Challenge US
Source: 1. Express Scripts; 2. Congressional Budget Office
The Evolving Biosimilar Landscape: Opportunities & Challenges 22 May 13, 2015 Content
• The Opportunity
• The European Experience
• The US Challenge
• Conclusions
The Evolving Biosimilar Landscape: Opportunities & Challenges 23 May 13, 2015 Four categories of players will mean very different go-to market strategies, pricing and competitive behaviour
Is there going to be space for everyone?
Innovator companies Generics companies Other players
Opportunity
(Fujifilm Kyowa Kirin Biologics)
EU Experience EU
US Challenge US
CRAMS* providers / Emerging market domestic players
Conclusion
*CRAMS, Contract Research and Manufacturing Services ** Based on press release news
The Evolving Biosimilar Landscape: Opportunities & Challenges 24 May 13, 2015 Success and speed of biosimilar uptake will also be dependent on the strategy employed by originators
Many R&D companies have launched or will launch next generation biologics
Originators New biologics Opportunity
Biosimilars (future generation)
New modern adalimumab insulins Gazyva cetuximab (obinutuzumab)
infliximab Experience EU
interferon rituximab Perjeta beta (pertuzumab) Lonquex
bevacizumab Challenge US
etanercept (lipegfilgrastim)
trastuzumab Kadcyla (trastuzumab SC Herceptin
insulins /drug Conclusion conjugate)
The Evolving Biosimilar Landscape: Opportunities & Challenges 25 May 13, 2015 The next 4-5 years will be pivotal
The way the industry as a whole will pave the way to it and continue building the learning curve will shape the uptake through 2020
2013 - 14 2015 - 17 2017 +
Building learning curve New wave of biosimilars: Converging towards a Opportunity
on existing biosimilars accelerating impact generic-like model
Biosimilar learning curve – 4 key drivers Generic-like scenario (automatic substitution limited to a few TAs) Business model design
1 Experience EU and alliance management
Commodity – Favorable framework like uptake Economies of learning on but moderate uptake 2 manufacturing and R&D Differentiated – like uptake Pre- and post-launch 3 Challenge US stakeholder management Biosimilar boom
delayed
Branding and go-to- 4 market strategy Development setbacks / post-launch
drawbacks Conclusion
The Evolving Biosimilar Landscape: Opportunities & Challenges 26 May 13, 2015 Please contact us for more information
Paul Villa Robert Rouse Senior Principal Senior Principal IMS Consulting Group IMS Consulting Group
[email protected] [email protected] +1 267 481 -1567 +1 267 481 -4667
The Evolving Biosimilar Landscape: Opportunities & Challenges 27 May 13, 2015 U.S. Biosimilars Law: An Update Hassen A. Sayeed, M.D. May 13, 2015
Presented To New York Pharma Forum
ROPES & GRAY LLP Disclaimer
This presentation represents solely the personal views of the author and does not reflect the view of Ropes & Gray LLP or any of its clients. It should not be construed as legal advice or a legal opinion on any specific facts or circumstances. This information is not intended to create, and receipt of it does not constitute, a lawyer-client relationship. The contents are intended for general informational purposes only, and you are urged to consult your own lawyer concerning your own situation and any specific legal questions you may have. While every attempt was made to insure that these materials are accurate, errors or omissions may be contained therein, for which any liability is disclaimed.
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Agenda
• The Biologics Price Competition And Innovation Act (“BPCIA”) Framework • Interpreting The BPCIA: The Pioneer Cases • Updates On FDA Guidance • Updates On CMS Guidance • Legal Impact Of Trade And Budget Issues
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What Is The BPCIA?
• Signed into law on March 23, 2010 as part of the Patient Protection and Affordable Care Act • Authorized coordinated changes to the Patent Act and the Public Health Service Act • Created an abbreviated licensure pathway for biological products that are “biosimilar” to or “interchangeable” with reference products already licensed by FDA (“Section 351(k) application”) • Applicants may rely on existing safety and efficacy data for the reference product sponsor (RPS) • RPS receives regulatory exclusivity -- usually 12 yrs
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The BPCIA Patent Dance
• Established a litigation enforcement scheme premised on a private, confidential exchange of patent information – An “early phase” litigation triggered by the filing of the abbreviated biosimilar application – A “late phase” preliminary injunction litigation triggered by a notice of commercial marketing of the biosimilar product • This complex and coordinated process of multiple exchanges has become known as the “patent dance”
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The Dance Card Is . . . Complex
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Some Simplified Steps
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“Early Stage” Litigation
20 days 60 days 60 days 60 days ? 30 days
Application Confidential RPS Patent Applicant RPS Negotiation Infringement Info to RPS List Response Reply Action • Within 20 days of biosimilar application acceptance for review by FDA, the applicant: – “Shall provide to the reference product sponsor a copy of” its application “and such other information that describes the process or processes used to manufacture the biological product that is the subject of such application.” 42 U.S.C. § 262(l)(2)(A). • Applicant may also provide additional information requested by reference product sponsor (RPS)
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20 days 60 days 60 days 60 days ? 30 days
Application Confidential RPS Patent Applicant RPS Negotiation Litigation Info to RPS List Response Reply • Within 60 days of receipt of application, RPS provides: – The list of patents owned or exclusively licensed for which a claim of infringement could reasonably be asserted; and – Identification of patents available for license • Failure to timely identify renders unidentified patents unenforceable against the biosimilar product
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20 days 60 days 60 days 60 days ? 30 days
Application Confidential RPS Patent Applicant RPS Negotiation Litigation Info to RPS List Response Reply • Within 60 days of receipt of RPS patent list, biosimilar applicant: – Must provide a “detailed statement” on a claim-by- claim basis for why the identified patents are unenforceable, invalid, or not infringed – Response to each offer to license the patents – May provide its own list of patents for which a claim of infringement could reasonably be asserted
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20 days 60 days 60 days 60 days ? 30 days
Application Confidential RPS Patent Applicant RPS Negotiation Litigation Info to RPS List Response Reply • Within 60 days of receipt of biosimilar applicant patent list and statement, RPS provides: – Detailed statement of why the identified patents are infringed, not invalid and/or enforceable
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20 days 60 days 60 days 60 days ? 30 days
Application Confidential RPS Patent Applicant RPS Negotiation Litigation Info to RPS List Response Reply • Biosimilar applicant and RPS negotiate in good faith concerning patents to be litigated • If agreement is reached within 15 days of beginning negotiations, RPS files suit within 30 days
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20 days 60 days 60 days 60 days ? 30 days
Application Confidential RPS Patent Applicant RPS Negotiation Litigation Info to RPS List Response Reply • If no agreement is reached within 15 days – Biosimilar applicant specifies number of patents to list for litigation • RPS may not list more patents than biosimilar applicant’s specified number (but may list a minimum of one) • Within 5 days, parties exchange lists identifying patents to be litigated • Within 30 days of exchange of lists, RPS files suit on all patents included on both lists
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• Biosimilar applicant “shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection [351](k)” 42 U.S.C. § 262(l)(8)(A). • Upon receipt of notice, RPS may seek preliminary injunction for any patent on the original list that was not subject of first round of litigation, or for a later- issued patent • Upon notice, either party may bring a declaratory judgment action on timely-identified patents that were not the subject of the first round of litigation
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• Published online at FDA in September 2014
• Contents – Date biologic product was licensed – Whether reference product exclusivity has been evaluated – Biosimilar or interchangeable determinations
16 ROPES & GRAY The Purple Book
• Information not provided – Dates of first licensure and exclusivity expiration not yet provided – No patent information – Not searchable
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Can Biosimilar Applicants Sue RPS Before FDA Filing To “Dance Early”?
• The answer appears to be no • Sandoz Inc. v. Amgen Inc. and Hoffman-La Roche • Remicade® Biosimilar Cases – Celltrion Healthcare Co. Ltd. v. Janssen Biotech, Inc. – Celltrion Healthcare Co. Ltd. v. Kennedy Trust for Rheumatology Research – Hospira, Inc. v. Janssen Biotech, Inc., et al.
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Sandoz Inc. v. Amgen Inc. and Hoffman-La Roche • Amgen’s BLA for Enbrel® (etanercept) licensed in 1998 • Sandoz began developing an etanercept biosimilar in 2004 and started FDA discussions in 2010 • After new patents covering Enbrel® issued and were licensed to Amgen, Sandoz filed a declaratory judgment suit in 2013 in N.D. Cal. seeking a determination of invalidity. • Sandoz was in Phase III testing at time of suit
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Sandoz Inc. v. Amgen Inc. and Hoffman-La Roche • District Court dismissed the suit for lack of subject matter jurisdiction in November 2013 • Sandoz’s application not yet filed • Interpreted BPCIA to preclude suit – “Sandoz does not contend, and cannot contend, it has complied with its obligations [under the statute] because . . . it has not, to date, filed an application with the FDA.” • Three years to get first case interpreting the BPCIA! • Case No. 3:13-cv-02904-MMC (N.D. Cal.)
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Sandoz Inc. v. Amgen Inc. and Hoffman-La Roche • Federal Circuit affirmed in December 2014 – Lack of subject matter jurisdiction – No real or immediate injury or threat to Sandoz because it had not filed its biosimilar application – Application could be altered or abandoned depending on Sandoz’s clinical testing and infringement issues could change • Case No. 2014-1693 (Fed. Cir. 2014)
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Sandoz Inc. v. Amgen Inc. and Hoffman-La Roche • Federal Circuit declined to address – Whether the BPCIA precluded Sandoz’s suit, which was an alternative ground for dismissal – If Sandoz had filed its application under the BPCIA, would the statute have foreclosed the lawsuit? • Is there otherwise independent jurisdiction when there is “sufficient immediacy and reality” for a suit?
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Remicade® Biosimilar Cases
• Janssen’s BLA for Remicade® (infliximab) licensed in 1998 • Celltrion developing biosimilar product co-marketed with Hospira • Prior to filing its Section 351(k) application, Celltrion filed a declaratory judgment suit against Janssen alleging that three Celltrion patents were improperly obtained
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Remicade® Biosimilar Cases
• Celltrion Healthcare Co. Ltd. v. Janssen Biotech, Inc., No. 14-11613 (D. Mass. filed Mar. 31, 2014) – Case voluntarily dismissed on October 24, 2014 before a ruling on Janssen’s motion to dismiss
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Remicade® Biosimilar Cases
• Celltrion Healthcare Co. Ltd. v. Kennedy Trust for Rheumatology Research, No. 14-2256, 2014 WL 6765996 (S.D.N.Y. Dec. 1, 2014) – Celltrion’s declaratory judgment action dismissed for lack of subject matter jurisdiction • “Celltrion is simply too far from receiving FDA approval . . . for the exercise of declaratory judgment to be proper” • “Even if the Court were to find … that the threat of injury was sufficiently demonstrable … the Court would still exercise discretion to decline to hear this case in light of the BPCIA statutory framework . . . .”
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Remicade® Biosimilar Cases
• Hospira, Inc. v. Janssen Biotech, Inc., et al. 113 U.S.P.Q.2d 1260 (S.D.N.Y. 2014) – Hospira’s declaratory judgment action dismissed for lack of subject matter jurisdiction • “[As with the Celltrion v. Kennedy Trust case], the existence of the BPCIA mechanisms for dispute resolution counsels against the exercise of jurisdiction over this complaint.” – Held even though Hospira was not BPCIA applicant – Decided after Celltrion had filed its Section 351(k) application with FDA and after the FDA accepted it
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Can Biosimilar Applicants Opt Out Of The BPCIA Dance? • The answer will be decided by the Federal Circuit soon • Amgen Inc. v. Sandoz • Janssen Biotech, Inc. v. Celltrion Healthcare Co., Ltd. (pending in District Court)
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Amgen Inc. v. Sandoz Inc.
• On July 7, 2014, Sandoz received notice that FDA had accepted its Section 351(k) application for Zarxio®, a biosimilar to Amgen’s Neupogen® (filgrastim)
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Amgen Inc. v. Sandoz Inc.
• Sandoz advised Amgen of the notification and proposed an alternative dispute resolution procedure to Amgen – Deciding not to disclose its application to Amgen – Decided not to exercise the “company’s right to use the patent information exchange process of the BPCIA”
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Amgen Inc. v. Sandoz Inc.
• Amgen argued that Sandoz’s use of the Section 351(k) pathway obligated Sandoz to use the BPCIA procedures for patent dispute resolution • On October 14, 2014, Amgen brought a declaratory judgment suit against Sandoz in the N.D. Cal. seeking to enjoin Sandoz from marketing Zarxio® until Sandoz follows the BPCIA • Complaint alleged unfair competition, conversion (unfair use of RPS data), and patent infringement • On March 5, 2015, the FDA approved Zarxio®
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Amgen Inc. v. Sandoz Inc.
• Amgen also filed a petition with FDA in October 2014 seeking a rule consistent with its litigation position – Section 351(k) applicants must provide RPS “with a copy of the application and information that describes the process(es) used to manufacture the biosimilar product that is the subject of the application” • FDA denied petition on March 25, 2015 – “Competing interpretations of [Section 351] are the subject of litigation that may clarify how [that section] should be interpreted”
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Amgen Inc. v. Sandoz Inc.
• On March 19, 2015, the District Court denied Amgen’s motion for preliminary injunction – Biosimilar applicant’s failure to comply with the BPCIA’s requirement that it “shall” provide the reference product sponsor a copy of the BLA is not actionable – A biosimilar applicant may (vs “shall”) give the sponsor 180 days’ notice of commercial marketing as required by the BPCIA prior to approval, and thus Sandoz complied with the statute • Zarxio® seemed poised for imminent launch
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Amgen Inc. v. Sandoz Inc.
• Amgen appealed to the Federal Circuit • Case No. 15-1499 (Fed. Cir.) – Amicus briefs supporting Amgen filed by Janssen Biotech, Inc., and AbbVie Inc. – Amicus briefs supporting Sandoz filed by Generic Pharmaceutical Association (GPhA), Hospira, Inc. and Celltrion, Inc. – Amicus brief supporting neither party filed by BIO
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Amgen Inc. v. Sandoz Inc.
• Sandoz had agreed to not launch Zarxio® until the earlier of May 11, 2015 or a Federal Circuit ruling on Amgen’s request for an injunction pending appeal • On May 5, 2015, the Federal Circuit granted Amgen’s motion for injunction pending decision on appeal • Oral argument set for June 3, 2015
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Janssen Biotech, Inc. v. Celltrion Healthcare Co., Ltd. • Celltrion advised Janssen that they would begin commercial marketing of their proposed biosimilar product as early as 180 days from the date of a notice issued on August 4, 2015 • Celltrion argued that notice to RPS at any time was appropriate because the BPCIA does not “include a condition precedent to providing notice.” • Celltrion’s product not yet licensed by FDA
35 ROPES & GRAY Janssen Biotech, Inc. v. Celltrion Healthcare Co., Ltd. • Janssen filed suit arguing that the effect of Defendants’ purported “notice” ignored the statutory 180-day window after license and before launch in which Janssen could seek a preliminary injunction • Case No. 15-10698 (D. Mass.) (Mar. 6, 2015) • Janssen filed its Motion for Partial Summary Judgment and a Preliminary and Permanent Injunction filed on April 8, 2015
36 ROPES & GRAY Unanswered Questions
• Can Section 351(k) applicants elect not to use the BPCIA framework? • Can a Section 351(k) applicants provide notice of commercial marketing before FDA licensure? • Are any parts of the BPCIA optional? • Is a Section 351(k) applicant obligated to turn its application over to the RPS? • What happens if the Federal Circuit doesn’t clear up all of these issues?
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Unanswered Questions
• Can the RPS compel compliance with the BPCIA? • Will the AG be invited to brief the issue?
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Updates On FDA Guidance
• On April 28, 2015, FDA released three final guidance documents regarding biosimilars • “Q&A On BCPIA Implementation” – Biosimilarity And Interchangeability • Addressed bridging studies and extrapolation of data to other indications – What Is A Biological Product? • Greater than 40 amino acids – Exclusivity • Pending question on how to seek 12 year exclusivity
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Updates On FDA Guidance
• “Quality Considerations In Demonstrating Biosimilarity” • “Scientific Considerations In Demonstrating Biosimilarity” – Technical issues • GOP Senators’ Letter on May 7, 2015 – Expressed “significant concern” about FDA’s use of draft guidances to make policy changes and the fact that draft guidances are not revised in a timely manner
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Updates On FDA Guidance
• GOP Senators’ Letter on May 7, 2015 – Asked for FDA response to questions relating generally to : (1) FDA turnaround time for guidances; (2) FDA activities to improve efficiency on guidance finalization and expert guidance; (3) mechanisms for making sure that staff do not follow draft guidance instead of other policy or final guidance • Senator Lamar Alexander (R-TN), Senator Richard Burr (R-NC), Senator Johnny Isakson (R-GA), Senator Orrin Hatch (R-UT)
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Unanswered Questions
• Labeling and naming conventions – Can a biosimilar’s generic name be the same as that of the reference product? (filgrastim vs. filgrastim- sndz) • Interchangeability – What is required to demonstrate interchangeability? • FDA plans to release five additional guidance documents by year-end 2015, including guidance on non-proprietary naming and statistical approaches on proving biosimilarity
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Updates On CMS Guidance
• On March 30, 2015, CMS issued guidance that could incentivize provider use of biosimilars – Physician-administered drugs are typically reimbursed as “buy and bill” – Average sales price (ASP) + 6% “spread” • In the generic small-molecule world, drugs are normally substitutable
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Updates On CMS Guidance
• When generics first come on the market, provider is initially compensated by ASP of reference product, which drives demand for generics – Generics eventually drive down ASP, which even further incentivizes adoption of generics • In contrast, biosimilars (including Zarxio®) are not interchangeable by default – Special rules about what is “interchangeable”
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Updates On CMS Guidance
• The 6% spread for biosimilars will be determined by the reference product ASP only
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Unanswered Questions
• Theoretically incentivizes providers to use the lower- cost product, but there may be complications arising from physician preferences and other market factors • Impact of state substitution laws
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Legal Impact Of Trade And Budget Issues • BPCIA provides 12 years of exclusivity from biosimilar competition for biologic reference products – Supporting letters written by 11 Governors and Congress members from both parties
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Legal Impact Of Trade And Budget Issues • However, ongoing negotiations over the Trans- Pacific Partnership Free Trade Agreement have complicated matters – Rules concerning biologics exclusivity “are one of the most difficult outstanding issues in the negotiations” • U.S. Trade Representative Michael Froman, January 2015 Senate Hearing • Further complications arising from potential disconnect between domestic and international protections
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Legal Impact Of Trade And Budget Issues • In FY2016 budget, the Obama Administration proposed reducing 12 year term to 7 year term for cost savings – Same proposal has been included in every budget since FY2011
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Thank You
Hassen A. Sayeed, M.D. Ropes & Gray, LLP 1211 Avenue of the Americas New York, New York 10036 (212) 596-9122 [email protected]
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Evolving Biosimilars Landscape: Opportunities and Challenges
South Korean Biosimilars
Tae-Wan Kim, Ph.D. Associate Professor Department of Pathology & Cell Biology Taub Institute for Research on Alzheimer’s Disease and the Aging Brain Columbia University Medical Center Contact: [email protected]
New York Pharma Forum
(May 13, 2015) 51 Introduction Of A Panel Speaker – Tae-Wan Kim, Ph.D.
• Korean-born scientist working on Alzheimer’s drug discovery (Phenotypic screening in physiological brain cells, hit and early lead discovery and new target ID)
• Current Interests: • Discovery alliance with a pharma on new Alzheimer’s disease targets • A startup company for developing a new MRI contrast agent devoid of gadolinium-associated nephrotoxicity
• Have worked as co-founder of two bioventures in US, consultant/advisor for a number of bio-pharma companies and VCs (e.g. advisor to one of the major biosimilar players in Korea at early phase)
• A big advocate of Korean bio-pharma industry!
52 Agenda
• Introduction – Korean Pharmaceutical Industry • Landscape – Korean Biosimilar Industry • Leading Biosimilar Players in Korea (Pipeline and Strategy) • Celltrion • Samsung Bioepis • Hanwha • LG Life Sciences • Dong-A • Green Cross • Future Outlook
53 South Korean Pharmaceutical Industry
• South Korea: Industrialized nation with population around 50.2 million • Market value: $19.3 billion in 2013 (expected to be $24.3 billion* by 2020, at a Compound Annual Growth Rate (CAGR) of 3.9%) • Demographics: Increasing demand for healthcare services from an expanding elderly population • Healthcare system: A high level of access to healthcare insurance and reimbursement Supportive and robust clinical infrastructure for clinical development and market entry • Government initiatives: Pharma Korea 2020 Roadmap Promotion of biosimilar (target: 22% of global market share) • Free Trade Agreement with the US in 2007 • A large pool of R&D experts to support pharmaceutical industry • Further expansion of generic industry • Need to foster innovative drug programs
54 *Source: GlobalData 2014 and personal research Korean Pharmaceutical Industry & Its R&D
Talented Human Resources World 11th Largest Economy Advanced IT Environment Korea Strategic Regional Location Opportunities Creativity & Innovation Systematic R&D Strategies in Biotechnology Harmonized R&D Collaboration Environment Strong Industrial Needs for Outsourcing & Partnership
55 Market Trends
Korean Biopharmaceuticals Industry at Glance 1. CAGR of biopharmaceuticals production: 22.3% (‘07~‘10) 2. 842 items approved (till 2012 Apr. 554 domestic, 298 imported) 3. More clinical trials: recombinant drug studies dominate 66.2%, cell/gene therapy research continued (13 cases(’09) 18 cases(’10) 15 cases (’11) 4. World-first stem cell therapeutics to get marketing approval: “Hearticell-AMT” of FCB Pharicell(‘11.7), “CardiStem” of Medipost (‘12.1), “CupiStem” of Antrogen(‘12.1)
. Conglomerates to set up/expand their biobusiness.
Company Subsidiaries & Affiliates Major Business Sector
Samsung Electronics U-healthcare, Biosimilar antibodies, new drug development Samsung Electro-Mechanics Customized anticancer drugs using cell chip Samsung Techwin In-vitro diagnostics Samsung Medical Center New biopharmaceuticals Samsung Advanced Institute of Technology Immunodiagnosis & Lab-on-a-chip Samsung SDS Bioinformatics Samsung Biologics Mass production of biopharmaceuticals (CMO)
Hanwha Chemical Biosimilar antibodies, new drug development LG life Science Biosimilar antibodies, new drug development
UB care U healthcare SK Chemical New drug development(natural, small molecule drugs)
Colon Life Science Cell therapeutics for degenerative arthritis Iljin Eletric Medical devices Source: InvestKorea 2012 Market Trends
. After patent expiration of original drugs (small molecule and biologics) Overall the generic drug market expanded 13% in 2010 (source : EvaluatePharma)
Generic Market of Korea (‘09-’10) Prospect of the Global/Korean Biosimilar Market
(Unit : 100M USD)
“ Global Top 8th ”
Source :Mylan 2011, VOI 2010, Stada 2011 (Based on 2010 exchange reate average), CGPA Source : “ South Korea: Generics and Biosimilars Overview Technical Insights, Datamonitor 2011, Deloitte 2010, Portai Brazil 2010, Chhabara 2011b, Datamonitor (2011.8), Industrial materials, HMC Investment,(2011)
th th . Korea’s market size : Top 8 in Global, Top 4 in Asia . Aggressive development policy of the government . Rapid growing domestic market : (‘10~’12) 7% CAGR . Investment size : US$1.4B(‘10)->$5B (‘15)-> $13.8B(‘20) . Relatively generous Drug Pricing System of Korea . Major Korean companies(Samsung, LG, Hanwha) are entering . From KFDA, total 388 of bioequivalent tests are approved in 2010. into the Bio-industry. Source: InvestKorea 2012 Market Status (Pharmaceutical Industry)
- Total sales amount of the local players, Dong-a, Daewoong, etc. are ranked at the top. - Among top 30 players, the major MNCs are over 1/3, including GSK, Novartis, Pfizer, etc.
Top 30 Players in Korean Pharma Market (Unit: KRW Billion, %)
Total Sales Total Sales Total Sales Rank Company Growh Rank Company Growh Rank Company Growh 2009 2010 2011 2009 2010 2011 2009 2010 2011 Rate Rate Rate Choong- Berna 1 Dong-A 801 846.8 907.3 7.1% 11 455.1 443.3 431 -2.8% 21 310 277.9 248 -10.8% wae Biotech LG Life 2 Daewoong 613.8 672.2 711.1 5.8% 12 327.3 334.3 372.5 11.4% 22 Dongwha 145.1 215.3 234.6 9% Science Bayer Janssen 3 Green Cross 643.2 791 698.9 -11.6% 13 342.4 342.8 355.5 3.7% 23 203.1 210.3 232 10.3% Korea Korea Sanofi- 4 Yuhan Co. 630.3 649.3 667.6 2.8% 14 Aventis 376.8 428 344 -19.6% 24 Shin Poong 207.9 225.7 224.9 -0.4% Korea 5 Hanmi 616 595 512.5 -13.9% 25 Roche Korea 312.1 252 218.9 -13.1% 15 Ildong 316.6 338 338.5 0.2% 6 GSK Korea 434.3 465 506.2 8.9% 26 Samjin 165.4 200.4 201.8 0.7% 16 Handok 293.4 321 333.2 3.8%
7 Novartis 362.6 435.8 478.8 9.87% Kwang 27 Wyeth Korea 149.8 161.7 184.2 13.9% 17 276.6 289.4 313.3 8.3% Dong Roche 8 Jeil Pharm 369.5 431.3 462.9 7.3% 28 136.6 143.7 170 18.3% 18 Boryung 267.8 301 308 2.3% Diagnostics
9 Pfizer 333.2 422.8 452.7 7.1% J&J 29 Dong Kook 123.2 140.4 160.3 14.2% 19 220.7 252.8 276.5 9.4% Medical Baxter 10 CKD Pharm 354.5 419.6 442.2 5.4% 30 131.9 138.1 153.9 11.4% 20 Astrazeneca 218.6 247.3 261.8 5.9% Korea
Updated ranks (2014): 1. Yuhan; 2. Green Cross; 3. Daewoong; 4. Hanmi; 5. Dong-A ST; 6. CKD
Source: InvestKorea 2012 based on each company’s annual report/DART (2012.6) Korea’s Infrastructure
High-Quality Korea (Seoul), Clinical the 2nd largest number of clinical trials in 2010 Researchers (2005- 77th , 2009- 9th) Source : KoNECT (2011, 5)
Approved Clinical Trials from KFDA Large Number of Multi-national trial, Local trial Patients
Better Medical Infrastructure
Cost-effective, (Rate of preclinical studies & phase I, II: >35%) Time-saving Samsung Medical CenterS 107 clinical trials of multinational companies (2010) SCI registered research paper : 280(2006) ->657(2010) Globa & Domestic Networks Asan Medical Center Network with Ludwig Institute for Cancer Research Emory University Institute, KAIST, Postec etc. Source: InvestKorea 2012 Korea’s Clinical Advantages
• Patent extension granted by participation in clinical trials • Fully introduced ICH-GCP and well-aligned local regulation for clinical trials • Protocol based review system (no requirement of Asian PK for conducting P2/P3 studies) • Comparatively short initiation time (2-3 months): MFDS can approve a clinical trial application within 30 working days when no further information is requested and IRB process is in parallel • Less translation burden: only protocol, ICF and some info of IB • Centralized patients and centers with experienced investigators (~160 accredited clinical trial sites) • The possible role as an Asian reference country • Future possibility for mutual recognition among East Asian countries: ongoing Korea-China-Japan tripartite discussions
Source: Dr. Deborah Chee, Korea National Enterprise for Clinical Trials (KoNECT) 60 Drivers of Biosimilar Industry in Korea
• Strong government supports: Willingness of the government to grow and help biotechnology industry as a next generation growth engine Announced to make huge investments the biosimilars industry Favorable business environment due to tax concessions, cash grant, site location support and financial support for pharmaceutical companies investing in Korea • Corporate initiatives: Country’s conglomerates (e.g. Samsung) are investing heavily in the business • Clinical development: A good medical infrastructure for reliable clinical trial studies • Regulatory affairs: Introduction of biosimilars guidelines consistent with the EMA model (2009) • Human resources: A large pool of highly qualified researchers and engineers in biotechnology
61 Challenges of Biosimilar Industry in Korea
• A small domestic market of biologics • Limited experience and capability in global marketing/sales • Limited experience in registration process in the advanced markets • Limited experience in dealing with innovator’s challenge • Insufficient bio-manufacturing capacity with cGMP and EUGMP quality • Commercial success has not been proven
62 Biosimilars Market Challenges in Emerging Markets
Lack of patent protection for high growth products (G-CSF and MAbs) Lack of patent rights in majority of the emerging countries for biologics like enbrel, TNF- alpha inhibitors creates a huge market.
Quality consciousness among doctors/physicians Huge patient potential in Doctors/physicians are loyal to ROW innovator molecules and can be EMERGING Breast cancer, non-Hodgkin's very fussy in switching MARKETS lymphoma (NHL), prescriptions. However, when autoimmune deficiencies price is concerned, a lower prices are out of control and most presents an attractive proposal if of the time, do not afford the similarity is established. biologics.
Lack of or low reimbursement for high priced biologics Emerging countries typically have poor insurance coverage.
63 Source : Frost and Sullivan Key Success Factors for Major Korean Biosimilar Players
• Major Korean biosimilar players are implementing:
• Scale: Major financial backing provided by major institutional investors and conglomerates • “No-more” Domestic-first approach: Alliances with global pharma, CRO or commercialization companies allow the access to the global market • Innovation is less critical in biosimilar sector as compared to first-in-class drugs
64 Biosimilar Regulatory Environment of Korea • South Korea has adopted the EU regulatory guidelines, which will put Korean companies in a strong position to export to highly regulated markets and also drive alliances between domestic players and foreign companies seeking to tap into South Korean production capabilities. • In line with the government’s policy to promote the biosimilars industry, the Korean Ministry of Food and Drug Safety (MFDS), is encouraging development of biosimilars by permitting a rolling BLA (biologics license application). This allows for sections of a BLA to be submitted on an ongoing basis if certain criteria are met.
Pricing/Reimbursement System in Korea • South Korea’s national health insurance system provides coverage for the majority of drugs entering the market. To obtain reimbursement companies must first obtain a cost-effectiveness review from the Health Insurance Review and Assessment Service (HIRA) following approval by the MFDS. After the review process, the reimbursable price is negotiated between the manufacturer and the National Health Insurance Corporation. Patient pharmaceutical co- payments are 20% and 30% for inpatient and outpatient treatment respectively, while those for orphan drugs are lower at 10%, and co-payments for cancer treatments were reduced from 10% to 5% of total drug expenditure from December 2009. 65 Korean Biosimilar Portfolio (2013) By The Numbers
Source: RA Rader. An Analysis of the US Biosimilars Development Pipeline and Likely Market Evolution.66 BioProvess International. 2013 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.
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. Image: pharmacokinetics comparison of CT-P13 versus infliximab 67 Source: Annals of the Rheumatic Diseases. 2013 Oct; 72(10): 1605–1612. Biosimilars Approved in South Korea’s Ministry of Food and Drug Safety (MFDS), formerly the Korean Food and Drug Administration (KFDA)
Product name Active Therapeutic area Authorization date Manufacturer/ substance Company name
Davictrel etanercept Ankylosing spondylitis 11 Nov 2014 Hanwha Chemical Psoriasis Psoriatic arthritis Rheumatoid arthritis
Herzuma trastuzumab HER2+ breast cancer 15 Jan 2014 Celltrion Advanced (metastatic) stomach cancer
Omnitrope somatropin Pituitary dwarfism Jan 2014 Sandoz Prader-Willi syndrome Turner syndrome
Remsima infliximab Ankylosing spondylitis 23 Jul 2012 Celltrion World’s first Crohn’s disease biosimilar Psoriasis antibody Rheumatoid arthritis approval Ulcerative colitis
Source: GaBI Online - Generics and Biosimilars Initiative. South Korean guidelines for biosimilars68 ; MFDS data updated on April 2015 EMA Approved Biosimilars
Product Name Active Substance Marketing Authorisation Holder Authorisation Date Abasaglar insulin glargine Eli Lilly 2014 Accofil filgrastim Accord Healthcare 2014 Bemfola follitropin alfa Finox Biotech 2014 Grastofil filgrastim Apotex 2013 Inflectra infliximab Hospira 2013 Ovaleap follitropin alfa Teva 2013 Remsima infliximab Celltrion 2013 Nivestim filgrastim Hospira 2010 Filgrastim Hexal filgrastim Hexal 2009 Zarzio filgrastim Sandoz 2009 Biograstim filgrastim AbZ-Pharma 2008 Ratiograstim filgrastim Ratiopharm 2008 Tevagrastim filgrastim Teva 2008 Abseamed epoetin alfa Medice Arzneimittel Pütter 2007 Binocrit epoetin alfa Sandoz 2007 Epoetin Alfa Hexal epoetin alfa Hexal 2007 Retacrit epoetin zeta Hospira 2007 Silapo epoetin zeta Stada 2007 Omnitrope somatropin Sandoz 2006 69 Source: European Medicines Agency. List correct as of April 20th 2015. Celltrion - Introduction
• Established 2002 as CMO; started to develop biosimilars in 2007 • Supported strongly by Korean government and located at a government-designated free economic zone, Inchon Songdo) • A front-runner in mAb biosimilars – CT-P13, RemsimaTM (InflectraTM in US, if approved), a biosimilar of J&J’s Remicade (Infliximab); CT-P06, HerzumaTM, a biosimilar of Roche’s Herceptin (Trastuzumab) • Celltrion Healthcare Co, distribution and marketing unit of Celltrion, Inc.: revenue of 145 billion won ($130.7 million) and operating profit of 39.3 billion won in 2013
70 Celltrion - History
Sep 2013 Jan 2010 EMA Approval Approval to begin Phase III trial in EU for CT-P13 Jan 2014 for HerzumaTM (breast cancer) MFDS Approval for HerzumaTM
Jul 2012 MFDS Approval for CT-P13 Jan. 2014 Canada Approval
Mar 2015 Feb 2002 Dec 2007 Dec 2010 FDA Inspection Foundation Plant 1 Mechanical completion of Jul 2014 nd for CT-P13 of Celltrion approval the 2 plant PMDA Approval from US FDA production Aug 2008 Inspection Jun 2005 IPO on the Korean stock Supply agreement of RA exchange, KOSDAQ treatment Abatacept with Bristol-Myers Squibb
71 Source: Satnley Hong, President, Celltrion Healthcare New Drug Biosimilar Biosimilar Candidates Candidates Product Celltrion CT CT CT CT CT CT CT Project Herzuma (CT Remsima Brand CT CT CT CT CT Project ------P14 P17 P16 P5 P15 P10 P6 - P24 P19 P25 P26 P27 P13)
®
- palivizumab adalimumab bevacizumab etanercept cetuximab rituximab trastuzumab INN trastuzumab infliximab INN SCW(JPN) CD n/a n/a CDC (US) Collaborators
Pipeline
C C (US/China)
Herceptin Remicade Ref. Enbrel Erbitux Rituxan Herceptin Ref. Synagi Humira Avastin
Product Product ® ® ® ® ®
®
Monoclonal Monoclonal antibody Monoclonal Cell culture AB drug Monoclonal Molecule type
® ® ®
conjugation RSV RSV infant rheumatoid arthritis, metastatic colon cancer rheumatoid arthritis colorectal cancer non metastatic Approved indications cancer metastatic psoriasis spondylitis, psoriatic arthritis, colitis, ulcerative disease, pediatric Crohn’s disease, rheumatoid arthritis, adult Crohn’s Approvedindications
vaccine antibody antibody - Hodgkin’s Hodgkin’s lymphoma
ankylosing
colitis, colitis, pediatric ulcerative
b b reast , gastric cancer reast cancer, gastric
hepatitis rabies virus influenza virus breast cancer influenza virus Target
Source: Crohn’s
B B virus
Satnley disease
Hong,President, Process Process Process Ready for non Global Current status Process Process Process Ready for non Ready for non Global Additional global Current status . . • • • • Current status EMA under preparation MFDS(KFDA) approved (2014) US and EU were approved. 59 EMA Approved (2013) MFDS(KFDA) approved (2012)
countries including KR
FDAin progress (2015) phase2 phase2 study phase3 study
development development development development development development - - - Celltrion clinical clinical study studyclinical studyclinical
Phase Phase 3 study
Healthcare
72
Celltrion - Strategy
• The best example of CMO tapping into biosimilar market by applying its product development and manufacturing expertise • Strategic partnerships with global CROs (PPD and Parexel) to improve product development capabilities • Strong development expertise and manufacturing capabilities (> 140K L, US FDA cGMP and EMA’s GMP standard) • Commercialization strategy: • Partnership with companies with established distribution network in developed country (e.g. Hospira in North America, Europe, and Oceania and Nippon Kayaku in Japan) • Local marketing partners in emerging markets (17 different companies worldwide) • Aim to capture up to 20% of sales of its target molecules in developed country and 50% in emerging markets • Competitions: Sandoz and Teva in developed countries, and producers of cheaper alternatives in emerging markets
73 Celltrion-Hospira Partnership
• Business cooperation agreement (2009) to co-market eight biosimilar products/candidates by Celltrion (five of which are incremental to Hospira's pipeline) covering United States, Europe, Australia, New Zealand, and Canada • Celltrion – Getting the large global distribution network of Hospira • Hospira – Expanding biosimilar portfolio (five of the Celltrion’s eight biosimilars are incremental to Hospira's pipeline) • Celltrion and Hospira will collaborate on manufacturing and supply of the products; after regulatory approval, the parties will co-exclusively market the drugs, with the products independently commercialized under each party's brand name • Launch biosimilar Inflectra in major European markets (24 countries) together, aiming to win a large share of the €2bn in European sales recorded by Remicade in 2013 • Hospira, now a subsidiary of Pfizer, is working with Celltrion to get a Remicade biosimilar on the US market (under the name of infliximab with 20-30% discounted price)
74 Samsung Samsung’s Growth Strategy
“Samsung” (South Korean conglomerate) pitched in “Bio- Healthcare industry”
Escalation of Biz-Plan with 3-phase
Phase 1 Phase 2 Phase 3
Construct of facilities Development of Innovative Production for Biosimilar • In 2011, USD 300 million Biologics • Manufacturing systems for investment from Joint Venture • Convergence of medical systems biosimilar in 2016 • Starting production within 2013 - R&D Investment in new drug • Exporting of biosimilars to USA, • Winning contract of overseas - Linking business with hospital and Europe, Asian country pharmaceutical clients medical device of the Samsung group
75 Samsung Biologics and Samsung Bioepis
Samsung Biologics (CMO) • Founded in 2011; Located in Incheon FEZ • Initial investment of $0.3 Billion; Long-term plans to invest about $2 billion • Biologics production capabilities: 30K L (2013 cGMP); 120K L (expected in 2016) • Global 2nd CMO by 2016 • Contracted with Roche, Genentech and BMS
Samsung Bioepis (Biosimilar arm) • Development & Manufacturing, Analytics capabilities, Clinical trials design and execution, Supply chain management, Marketing skill, Medical & lifestyle safety
Samsung electronics and two other Samsung companies
97.05% 2.95% Samsung Biologics Quintiles Asia
90.3%
9.7% Samsung Bioepis Biogen-Idec 76 Samsung Bioepis – Pipeline & Alliance
• SB4 (Jan 2015) and SB2 (March 2015) have been submitted to EMA
• Biogen-idec exercised their option on SB2 in European market (December 2014) • Biosimilars Development and Commercialization Agreement between Merck (MSD, outside of US and Canada) and Samsung Bioepis • Merck – commercialization • Samsung Bioepis - preclinical and clinical development, process development and manufacturing, clinical trials and registration • Samsung Bioepis will receive an upfront payment from Merck, product supply income and will be eligible for additional payments associated with pre- specified clinical and regulatory milestones. 77 Hanwha Chemical
• Hanwha: One of the top 10 conglomerates in Korea by revenue • HD203, a biosimilar version of Enbrel (etanercept): • Approved in Korea (2014) • $720m biosimilar deal with Merck in 2011 (till 2024) but terminated in Dec 2012 (Sacking 4 top executives in Hanwha bio division) • Licensed out to Merck Serono (2015) • HD201, Herceptin biosimilar, P1 in Korea • Planned to build 7K L facility and had a contract with Korea Biotechnology Commercialization Center (KBCC) for manufacturing
78 LG Life Sciences
• LG Life Sciences (LGLS), a spin-off from LG Group conglomerate in 2002 • The first South Korean biopharmaceutical company to enter the EU market with its hGH biosimilar, which is marketed by its Swiss partner, Biopartners GmbH, as Valtropin (April 2006) • Pipeline: • LB03002 (EutrophinTM, hGH), marketed in Korea and US • Eutrophin-Plus (long-acting hGH), marketed in Korea and NDA in US • LBEC0101, Embrel biosimilar (etanercept), P1 completed in Korea • LBAL, Humira biosimilar, preclinical in Korea
79 Dong-A’s Biosimilars
Dong-A Pharmaceutical Co., Ltd.
Biosimilar JV with Meiji Seika Pharma (DMBio)
80 Current Dong-A (Socio Holding) Biosimilar Pipeline Status
Current status (as of May. 2015) Non-clinical Project Indication 200L CMC PK/PD & Cell line Ph 1 Ph 3 NDA MCB/WCB data Toxicity Screening package study
DA-3880 Anemia due to ® - Chemotherapy (Aranesp BS) - Chronic renal failure
Non–small cell lung cancer DA-3114 Metastatic CRC/RCC/breast can. (Avastin® BS) Advanced ovarian cancer Glioblastoma
DMB-3111 Breast cancer (Herceptin® BS) Metastatic stomach cancer
Rheumatoid arthritis DMB-3113 Psoriasis vulgaris /arthritis ® Ankylosing spondylitis (Humira BS) Juvenile idiopathic arthritis Crohn’s ds., Ulcerative colitis
Rheumatoid arthritis Psoriasis DA-3853 Psoriatic arthritis (Enbrel® BS) Ankylosing spondylitis Juvenile idiopathic arthritis
81 Green Cross Biosimilar Products: Strong Recombinant Protein Portfolio
82 Additional Biosimilar Players in Korea
• Isu Abxis • Established in 2000 as a subsidiary of Isu Chemical Co. Ltd. • Clotinab: Marked in Korea; Fab fragment of a therapeutic antibody for GP IIb/IIIa receptor; used as an adjunct to percutaneous coronary intervention (PCI) for prevention of cardiac ischemic complications • ISU-302 (Abcertin), biosimilar of Cerezyme (Genzyme) and Fabagal, a biosimilar of Fabrazyme (Genzyme), both of them marketed • ISU-103, Herceptin biosimilar, preclinical • ISU-202, Humira biosimilar, preclinical • Dong-A ST • DA-3801 (FSH): Marketed in Korea • DA-3031 (PG-G-CSF): Marketed in Korea • DA-3803 (hGH), P3 completed in Korea • DA-3030 (G-CSF), P2 completed in Korea • DA-3051 (Interferon-alpha), P1 in Brazil • DA-3880 (Darbepoetin-alpha), preclinical, licensed out to Japan
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Additional Biosimilar Players in Korea (also CMO)
• Aprogen • AP032, a biosimilar of Amgen’s Aranesp (Darbepoetin alfa): P3 in Korea; Partnering with Nichi-Iko for Japan (Nichi-Iko acquired a 33.4% stake in Aprogen in October 2010) • CKD • CKD-11101, Aranesp biosimilar: P1 in Korea • CKD-12101, PG-G-CSF, a biosimilar of Amgen’s Neulasta (Pegfilgrastim), preclinical • Daewoong • DWP422, Embrel biosimilar: P1 in Korea • Binex • CMO that manages Korea Biotechnology commercialization Center (KBCC) from Korea's Ministry of Knowledge Economy • Genexine • Established JV with Ajinomto for manufacturing and sales of serum free medium for biologics (Located Incheon FEZ)
84 “Bio-Betters” or “Super Biosimilars” (Fc fusion): Representative Players and Pipeline in Korea
• Hanmi Pharm • Lapscovery technology • Efpeglenatide (HM11260C) (long-acting Exendin-4 analog, P2 completed); LAPSInsulin 115 (HM12470) (Long-acting insulin analog, P1 completed); LAPSInsulin Combo (long-acting Exendin-4 and insulin combo, P1 ready); eflapegrastim(HM10460A) (Long-acting G-CSF analog, P2 completed, licensed out to Spectrum in US and Luye in China); LAPSrhGH(HM10560A) (Long-acting rhGH, P2 completed); LAPSGLP/GCG(HM12525A) (Long-acting GLP/GCG analog, P1 completed) • Alterogen • NexP fusion technology • hGH-NexP (P1); FVIIa-NexP (scale-up); Exenatide-NexP (process development); NexP-BP3m (cell line) • Biosimilar pipeline: Etanercept, Trastuzumab and Adalimumab biosimilars (Cristalia, Latin America partner); Aflibercept biosimilar (Kissei, Japan partner) • Genexine • HyFc (Hybrid Fc) technology • Pipelines: GX-E2 (long-acting EPO, P2); GX-H9 (long-acting H9, P2); CX-G3 (long-acting G-CSF, P1) 85 Outlook for Major Korean Biosimilar Players in Global Market
• Continuation of strong government support • Favorable clinical development and regulatory environment • Brand recognition and early entrant advantages • Growing biologic manufacturing capabilities (BMCs) • Accumulating clinical trial experiences and less knowledge hurdles in market, patent, and other regulatory issues • More efficient R&D, manufacturing, and marketing needed • More competitions (Teva and Sandoz in developed country; companies with cheaper alternatives in emerging markets)
• South Korean biosimilar companies will contribute substantially to future global markets.
86 Thank you!
87 Health & Welfare Dept.
Japanese Government Standpoint on
Biosimilar Use in Japan
Director of Health & Welfare Dept. Hiroyuki Kawabata
1 Definition of Biosimilar • "Biosimilars" are drugs which are confirmed to possess efficacy and safety identical to a biotechnology application drug approved in Japan by clinical trial. • Biotechnology application drugs are drugs which have an active ingredient of "DNA recombination protein" such as human growth hormone, insulin and antibody. Using the ability to make the protein in which a microorganism and a cell have these, it's produced. Biosimilar Generic Medicine Molecule Structure Huge and Complicated Small and Simple Validity and Safety Mostly same as the preceding Same as the preceding medicine medicine. Clinical trial Required Not required Development cost and High Low manufacturing equipment cost Price difference with the brand- Huge Small to Huge name drug The number of lists of articles included in drug price standard 25 (4 ingredients) 8,968 (as of December 2015) 89 Source: Made based on material of the Ministry of Health, Labour and Welfare A Glance at Biosimilars Adopted by Japanese Health Insurance
Category Brand-name Biosimilar Genotropin Tc Somatropin Growth Hormone (Pfizer) (Sandoz) 5.33mg : 36,410 Yen (~$304) 5mg : 24,930 Yen (~$200) ESPO Epoetin Alfa Blood Creation Hormone (Kyowa Hakko Kirin) (JCR Pharma) 3000 IU : 3,292 Yen (~$27) 3000 IU : 3,071 Yen (~$25) GRAN Filgrastim Leukocyte Growth Factor (Kyowa Hakko Kirin) (Mochida Pharma, Nippon Kayaku, others..) 75μg : 9,481 Yen (~$79) 75μg : 6,143 Yen (~$51)
Tumor Necrosis REMICADE Infliximab (Tanabe Mitsubishi Pharma) (Nippon Kayaku) Factor Blocker 100mg : 89,536 Yen (~$747) 100mg : 59,814 Yen (~$499)
90 Source: Made based on material of the Ministry of Health, Labour and Welfare Shift to Biotechnology Application Drugs
Market scale
【Trends in the Global Drug Market】
Biosimilar $19 billion
Biotechnology $190 billion application drug Biotechnology $90 billion application drug
$800 billion Molecular Growth in especially molecular developing country $891 billion drug drug
2010 2015 Year
91 Source: Made based on material of the Ministry of Health, Labour and Welfare Japanese Government’s Biosimilar Policy
Biosimilar prices are lower than the original brand-name drug prices. On the other hand, Biosimilar prices are still higher than other generic medicine prices because of expensive development cost and manufacturing difficulty.
In order to have a Biosimilar approved by PMDA, applicants are required to do clinical trials because of the huge and complicated molecule structure as opposed to small molecule pharmaceutical products.
The Japanese Government tries to promote use of generic medicine, including Biosimilars.
As a result of promoting biosimilar under the appropriate usage of direction of doctor, it hopes to cut medical expenses as well as the cost of pharmaceutical industry development.
92 Road map for further use promotion of generic medicine • To promote further use of generic medicine, Japanese Ministry of Health, Labour and Welfare created and published “Road map for further use promotion of generic medicine" on April 5, 2013. In this road map, Biosimilar is included in the category of generic medicine. • The new road map establishes the following new target for use of generic medicine and improves monitoring Japan’s annual share of the generic medicine aims to be more than 60 % by the end of March, 2018. Activity is monitored for further use in the promotion of generic medicine. Additional effects in promotion are taken based on observations.
Change and Target of the National Share of Generic Medicine Each Country’s Share of Generic Medicine (2010)
70.0% 100% 90% 60.0% 60.0% 91% 80% 82% 50.0% 70% 73% 46.9% 60% 40.0% 62% 39.9% 50% 30.0% 34.9% 35.8% 32.5% 40% 20.0% 30% 40% 20% 10.0% 10% 0.0% 0% 2005 2007 2009 2011 2013 2018 Japan U.S.A Germany England France
Copyright 2013 IMS Health 93 Source: Made based on material of the Ministry of Health, Labour and Welfare Concrete pillar of use promotion of generic medicine
1. Stable supply
2. Security of quality
3. Security of the reliability of quality
4. Offer of information to medical expert
5. Spread and Enlightenment
6. Evaluation of the medical treatment reward
7. Revision of drug price standard 94 New generic medicine’s national health insurance drug list
Policy Biosimilars are priced based on an older model for generics Oral: Priced at 70% the price of the Brand-name if there are less than 10 competitors, otherwise they are priced 60% the price of the Brand-name Injection: Always priced at 70% the price of the Brand-name Generics are priced on a new model approved by the Central Social Insurance Medical Council (12/25/2013) Oral: Priced at 60% the price of the Brand-name default and 50% if there are more than 10 competitors Injection: Always Priced at 60% the price of the Brand-name Brand-name New generic Before drug medicine
×0.7（0.6）
2014FY revise Brand-name New generic Now drug medicine ×0.6（0.5）
Source: Made based on material of the Ministry of Health, Labour and Welfare95 Health & Welfare Dept.
Thank you for your attention!
JETRO New York Health & Welfare Dept. Tel: (212)997-6471
The presenter and JETRO don't guarantee this document about anything such as utility, accuracy and an intellectual property right. lecture contents include private views, and are not the official government view. If suffering damage by use of information on this document, a writer and JETRO don’t have any kind of responsibility.
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