Case study-cmc challenges when a small biosimilar developer must rely on outsourcing for development and manufacturing

Transcription

1 CMC Workshop April 24-26, 2017 Case study-cmc challenges when a small biosimilar developer must rely on outsourcing for development and manufacturing Patricia Seymour Session 07B 1

2 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to DIA, its directors, officers, employees, volunteers, members, chapters, councils, Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. DIA and the DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. 2

3 Market Dynamics Favor Biosimilars Growth Global Trends in the Pharma and Health Care Fields 1 Global pharmaceutical sales forecast to reach ~$1.4T by 2020 Currently, biologics drug expenditure already accounts for ~28% a of pharmaceutical spend and are >33% of all drugs in development MAbs are largest and fastest growing segment 2 Continuous financial pressure on healthcare systems to make significant and sustained cost reductions US healthcare spending by 2025 forecast to be ~20% GDP 3 Major biopharmaceutical products are losing patent protection coupled with new regulatory approval pathways for biosimilars in major markets Biosimilar market is expected to grow to ~$40 billion by 2020 a a IMS: Delivering on the Potential of Biosimilar Medicines Mar 3

4 Biosimilars Market is Highly Competitive Global and large regional generic-drug companies dominated the first-wave biosimilars approved in Europe Teva, Sandoz, Stada, and Hospira account for more than 70% of the biosimilars approvals in 1 st wave Dominance of the large companies reflects the high cost of developing biosimilars as well as the need for established infrastructure and experience to generate sales Pharmsource 2016 Transition underway from early recombinant proteins to MAbs and competition is significant Biosimilars may represent a big eventual market opportunity, but CDMO-dependent developers may be at a disadvantage to established global bio/pharma companies. Significant growth of programs targeting developed markets 4

5 Current Manufacturing Landscape for Biosimilars ~66% of the first wave of approved biosimilars in Europe manufacture bulk drug substance (DS) in-house ~45% of the first wave approved biosimilars in Europe perform the fill/finish in-house For the second wave of biosimilars, manufacturing arrangements appear that ~55% possess large molecule DS manufacturing capability ~33% have a joint venture partner or licensor that has manufacturing capability Many joint ventures involve partners with manufacturing assets in Asia, including Mylan with Biocon (India), Hospira with Celltrion (South Korea), Biogen/Idec with Samsung Bioepsis (South Korea), and Oncobiologics with Strides Arcolab (Malaysia). Small biosimilar developers and CDMOs must develop a strategy that enables them to participate more meaningfully in the third wave of the biosimilar opportunity that will begin in 2020 Proprietary cell line and expression technologies, which help them deliver biosimilar DS more quickly and cheaply than in the past Strengthened analytical capabilities. But, how far can a biosimilar developer stray from the innovator technology? 5

6 Biopharmaceuticals/Biosimilars are Produced through a Complex Series of Steps 1. Isolate and identify the genetic code of the therapeutic protein. 2. Insert the genetic code into a living cell. 3. Isolate specific cells that have integrated the genetic code of the therapeutic protein into their genome and produce large quantities of the target protein. 4. Isolate the therapeutic protein from the cells and other nutrients through a series of purification processes. 5. Package protein into sterile vials. Different Process Different Product? Source: Slide by Nanna Aaby Kruse, Mediacademy, Oct

7 Inherent Variability of Biopharmaceutical Products It is not possible to make an identical copy of a reference product given the inherent structural and functional variability of biopharmaceutical products. Biosimilars must fall within a range of values across important structural and functional parameters compared to those of the reference drug. V L E V H C L D O D V L and V H are the variable regions which together comprise the antibody recognition and binding site C H1 G D O Hinge Region Identification of Known Post-translational Modifications (total number) D Deamidation (Asparagine) (6) E Glutamate or Pyroglutamate (2) C H2 G Carbohydrate Disulfide Bond G Glycation (4) Glycosylation (5+5) K Lysine or Des-lysine (2) C H3 O Oxidation (Methionine)(2) K From Kozlowski and Swann 2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600 (9600) Variants 7

8 Biosimilarity is Based on the Totality of Evidence CMC is the first, and most crucial, step in establishing biosimilarity to an innovator s marketed product 8

9 Example Case Study Development of infliximab Biosimilar by Small Developer Relying on CDMOs Infliximab is a chimeric human-mouse IgG1 kappa monoclonal antibody targeting TNF-α Reference product manufacturing process Expressed in S/P2.0 murine myeloma cell line Continuous perfusion cell culture Seven step down stream purification process Remicade (Centocor/Janssen, infliximab) has been marketed in the US since 1998 Inflectra (Pfizer/Celltrion, infliximab) approved for US sale in April 2016 and EU sale in Sept 2013 Flixabi (Samsung Bioepis, infliximab) approved for EU sale in May

10 So, Where Does a Small Developer Begin Working with a CDMO to Develop an infliximab Biosimilar? Considerations When Selecting a CDMO Speed and Cost Greater portion of time is spent upfront developing a process and characterizing a biosimilar molecule Once in clinical testing, timeline to commercialization will be faster than that of an innovator molecule Cost of goods (CoG) must be low for a biosimilar to compete in the market with comparator molecules Need for existing commercial manufacturing capabilities No time for technology transfers Need appropriate scale Need available capacity FTE equivalents approach Allows rapid turnaround and responsiveness Exclusivity / non-compete contract / Quality Agreements One-stop-shop 10

11 Developing the Process to Achieve Biosimilarity Match the innovator s manufacturing process as much as possible, such as the choice of cell line, use of the same formulation excipients, etc. All MAbs and cept fusion proteins used in rheumatology have had changes in their manufacturing processes after initial approval Collect numerous batches of the innovator s drug product over many years Celltrion collected 41 lots of EUapproved Remicade and 45 lots of USlicensed Remicade to compare against their biosimilar version Number of Process Changes Since Initial Approval Schneider, C. K. (2013) 'Biosimilars in rheumatology: the w ind of change in Ann Rheum Dis, England:

12 When Old Technology Just Won t Do BUT often the innovator s technology is 20+ years old and many advances have been made in cell line development and processes since then Better cell line technologies Many technologies being adopted by industry today enable more flexible operations First Movers Second tier General acceptance Aging Technologies Outsourcing to CMOs is another flexibilityenabling strategy of importance to industry Adapted from: Morten Munk, NNE Pharmaplan: Continuous Bioprocessing What is holding the industry back from implementing CBP more broadly? 12

13 Facilities of the Future? Manufacturing and Technology Trends Flexible Courtesy: KSep Modular Disposable From Aspen Brook Alert Survey, Oct 10, 2014 Continuous Courtesy: Pall Corp Simulated moving bed Courtesy: Tarpon Biosystems 13

14 Additional Challenges Access to Manufacturing Capacity Most CDMOs are in high demand, not just for biosimilar products Limited manufacturing know-how Lack of leverage with buyers A single digit market share might seem attractive to a small company but payers may not want to deal with an unproven supplier with a single product It remains to be seen just how many players the field can accommodate once it matures 2016 Rank Manufacturing Capacity Control 2021 Rank Company 2016 Volume (1,000s L) 2021 Volume (1,000s L) 1 1 Roche Lonza Johnson & Johnson Sanofi Boehringer Ingelheim Amgen Biogen Pfizer Celltrion Lilly Samsung Bristol-Myers Squibb Novartis All Others (120/128) 1,214 (33%) 2,106 (39%) Source: BPTC biotrak 14

15 Summary Challenges of Developing a Biosimilar via an Outsourcing Strategy Ability to achieve biosimilarity can be at risk if manufacturing technologies different from the innovator are selected Speed, Cost and Access to Capacity are major impediments to successfully developing a biosimilar and being a serious competitor Industry is consolidating via acquisition, atrophy and partnerships leaving some small developers without a dance partner 15

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