1. New York Washington Seattle Brian J. Malkin, Partner (bmalkin@flhlaw.com) Brian J. Malkin, Partner (bmalkin@flhlaw.com)bmalkin@flhlaw.com Frommer Lawrence & Haug LLP FDA Lawyers Blog (http://www.fdalawyersblog.com) INNOVATIVE STRATEGIES FOR NEW DRUG DEVELOPMENT BIOBETTERS Korea-Maryland, USA Bio Expo 2013 November 8, 2013

2. © 2013 Frommer Lawrence & Haug LLP KEY TOPICS  Identifying opportunities to extend into the marketplace.  Resources necessary for the production of biobetters.  Assessing the risks and benefits of producing a biobetter. 2

3. © 2013 Frommer Lawrence & Haug LLP WHAT IS A BIOBETTER?  A biological product related to an already-approved biological product but superior in one or more product characteristics.  The term “biobetter” became popular in the context of the Biologics Price Competition and Innovation Act (“the Biosimilars Act”).  Faced with rigorous requirements for biosimilarity and interchangeability in the Biosimilars Act, many applicants have expressed interest in biobetters. 3

4. © 2013 Frommer Lawrence & Haug LLP WHY IS IT “BETTER”?  Product characteristics targeted for improvement  Longer product half-life  Less frequent dosing  Lower likelihood of aggregation  Greater efficacy  Greater purity  Fewer adverse events  Streamlined manufacturing  Longer shelf-life  Easier administration/packaging improvements. 4

5. © 2013 Frommer Lawrence & Haug LLP LEGAL FRAMEWORK  It does not appear that FDA would approve a “biobetter” under the Biosimilars Act. A full BLA is likely required.  The Biosimilars Act does not use the term “biobetter”.  The Biosimilars Act authorizes FDA to approve biological products that are “biosimilar” to an already-approved biological product only under certain circumstances.  “Biosimilar” is defined as “Highly similar to the reference product notwithstanding minor differences in clinically inactive components.” “No clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.” 5

6. © 2013 Frommer Lawrence & Haug LLP MODIFICATION STRATEGIES Modification strategies include:  Chemical modification  PEGylation  Glycosylation  New formulation  Controlled release  New routes of administration (e.g., transdermal, nasal)  New manufacturing process  Use of new cell platform. 6

7. © 2013 Frommer Lawrence & Haug LLP Some areas of opportunity may include:  Monoclonal antibodies  Glycoproteins  Vaccines  Protein hormones. 7 IDENTIFYING OPPORTUNITIES

8. © 2013 Frommer Lawrence & Haug LLP IDENTIFYING OPPORTUNITIES (cont’d)  Possible improvements to antibody products  Further humanization  Minimizing murine sequences and maximizing human sequences  Increased number of binding targets  Bispecific antibodies  Antibody-drug conjugates  Links to cytotoxic drugs for targeting to cancer cells  Antibody fragments  Smaller versions of full-size marketed antibodies  May provide manufacturing advantages. 8

9. © 2013 Frommer Lawrence & Haug LLP  Possible improvements to glycoprotein products:  PEGylation  Altered glycosylation pattern  Altered amino acid sequence  Fusion with albumin or carrier protein  Use of controlled release technology  Improvements often focus on improving half-life. 9 IDENTIFYING OPPORTUNITIES (cont’d)

10. © 2013 Frommer Lawrence & Haug LLP IDENTIFYING OPPORTUNITIES (cont’d)  Vaccines  Switch from live, attenuated, or inactivated to recombinant products  Addition of adjuvants  Newer cell culture manufacturing methods  Increasing serotype number (i.e., broader spectrum of activity).  New delivery methods  E.g., oral, intranasal, transdermal. 10

11. © 2013 Frommer Lawrence & Haug LLP IDENTIFYING OPPORTUNITIES (cont’d)  Protein hormones  Insulin is a key target.  Much focus remains on modes of administration.  Orally-administered (e.g., Oramed’s ORMD 0801, Phase II trials).  Inhaled (e.g., Mannkind’s Afrezza ® ).  Transdermal. 11

12. © 2013 Frommer Lawrence & Haug LLP  Biobetters require similar resources necessary for the production of biosimilars.  Patent analysis and litigation capabilities  Research and development capabilities  Analytical capabilities  Clinical trial capabilities  Marketing capabilities. 12 BIOBETTER RESOURCES

13. © 2013 Frommer Lawrence & Haug LLP  Benefits  Greater potential to avoid infringing patents or lower litigation costs.  R&D costs to develop a biobetter may be less than for developing a new biological product.  “Better” attribute(s) are preferred to the reference listed product.  Potentially entitled to 12 years of exclusivity under the Biosimilars Act (FDA request likely required.).  Biosimilars Act suggests more stringent requirements for biosimilars (especially for interchangeable rating) than biobetters. 13 BIOBETTER PROs

14. © 2013 Frommer Lawrence & Haug LLP  Risks  Sophisticated patent analyses or litigation costs still may be required.  R&D costs are still high relative to drugs and some biosimilars.  12-year exclusivity not guaranteed and no exclusivity vis-à-vis other biobetters filed as original BLA products.  Marketing requirements may be high, especially to convert patients from referenced product to biobetter. 14 BIOBETTER CONs

15. © 2013 Frommer Lawrence & Haug LLP QUESTIONS? 15 Brian J. Malkin Partner, Frommer Lawrence & Haug LLP Editor, FDA Lawyers Blog 202-292-1530 bmalkin@flhlaw.com bmalkin@flhlaw.com http://www.fdalawyersblog.com