Amy S. Rosenberg, MD Director, DTP

1. The Division of Therapeutic Proteins:Regulatory and Research ProgramsCellular, Tissue, and Gene Therapies Advisory Committee Meeting, April 17, 2013 Amy S. Rosenberg, MD Director, DTP

2. Mission Statement The Division of Therapeutic Proteins (DTP) is responsible for protecting and advancing the public health by assuring the quality, safety and efficacy of biological therapeutic products, helping to ensure their security, and helping to speed innovations that make them safer, more effective and available.

3. The Future of Drug Safety: Promoting andProtecting the Health of the Public (Institute of Medicine Report 2006) “The committee affirms that a strong program of intramural scientific research provides an essential foundation for sound, scientifically based regulatory policy and performance”

4. Commissioner’s StatementsMargaret A. Hamburg, M.D., Commissioner of Food and Drugs, AAAS Forum on Science and Technology Policy May 14, 2010 • “But not only is more scientific knowledge required, but also a culture in which many scientific perspectives and opinions are sought and brought to bear on complex regulatory science problems.” • “No matter what, FDA must be a science based, science-driven agency in all we do.”

5. Benefits of Researcher-Reviewer Model: Credibility of Regulation • Hands on expertise for novel technologies, scientific approaches; insight into on and off target mechanisms of action; enhances regulatory evaluations • Interactions with scientists in academia and industry facilitate acceptability of regulatory recommendations and policies • Direct access for addressing critical regulatory questions that require research investigation

6. Division of Therapeutic Proteins, CDER, FDA Gibbes Johnson Deputy Division Director (Acting) Amy Rosenberg Division Director Serge Beaucage Chief, Lab of Chemistry (Acting) Daniela Verthelyi Chief Lab of Immunology Susan Kirshner Branch Chief I (Acting) Emanuela Lacana Branch Chief II (Acting) Kathy Lee Branch Chief III (Acting) Associate Chief Lab of Chemistry TBD Associate Chief Lab of Immunology TBD Secondary Reviewer TBD Secondary Reviewer TBD Serge’s lab Staff Daniela’s lab Staff Juhong Liu Gibbes Johnson PI Amy Rosenberg PI Full Time Reviewers Full Time Reviewers Full Time Reviewers Lab staff Lab staff Baolin Zhang PI Mike Norcross PI Lab staff Lab staff AshutoshRao PI Ed Max PI Lab staff Lab staff Jack Ragheb PI Lab staff Ray Donnelly PI Lab staff

7. Scientific Activities of DTP • Weekly seminar series: DTP and outside speakers • Site visits every 4 years; yearly evaluation for mission relevance and scientific productivity • Participation in NIH Scientific Activities: interest groups, retreats, seminars and journal clubs, symposia, study sections, advisors for initiatives. • Participation in FDA Scientific Activities: science rounds, Research Coordinating Committee, Science Forum, Promotion and Conversion Evaluation Committee, Adventitious Agent Working Group (with CBER) • Service on Editorial Boards of Journals, Reviewers for journals • Internal Research Grants Evaluation and Awards: Critical Path, Office of Women’s Health, Regulatory Science Research, Medical Countermeasures

8. Not the NIH, not Academia… • Most research personnel have significant regulatory load: • Dramatic increase in regulatory load including novel regulatory paradigms eg biosimilars • Non-research workload not predictable; can’t be managed as in academia • Limited ability to hire support staff (internal grants) • Research productivity affected across the division

9. Major Regulatory Scientific Challenges Confronting DTP • Comparabilityof biological therapeutics following manufacturing changes by same manufacturer: • seemingly minor manufacturing changes can have major impact on critical product attributes and clinical behavior • Biosimilars: same class therapeutic protein product produced by different manufacturer: physicochemical and biological similarity to innovator product reduce the number/dimensions of clinical trials needed for approval • DTP provides recommendations regarding the extent of pre-clinical and clinical studies to evaluate similarity in safety/efficacy based on the extent of physicochemical comparability • All biosimilars require a clinical immunogenicity study: DTP/LI scientists consult on immunogenicity evaluations of candidate biosimilar products

10. Biosimilar Applications in DTP 18 preIND/INDs in the Laboratory of Chemistry 5 reference products Much more intensive review than other IND/pre IND applications: coordinated meetings by Biosimilar Review Committee (5 meetings total) Dr. Johnson overseeing DTP’s biosimilar review Participation of DTP staff on Biosimilar policy issues and guidance documents LI reviewers perform immunogenicity reviews on all biosimilar products 10

11. Major Regulatory Scientific Challenges Confronting DTP: Requirement for Scientific Expertise • Biobetters: engineered versions of prototype products to enhance PK or other product characteristics • Enhanced PK/PD: pegylation, hyperglycosylation • Enhanced substrate binding: site directed mutagenesis (eg enhanced fibrin specificity) • Enhanced cellular targeting : use of receptor specific ligands or glycoform engineering for improved uptake in target cells • Novel technology products • Nanotechnology • Ankyrin repeat domains and avimers • Device/biologic combination products • Breakthrough Therapeutics: FDA Safety and Innovation Act (FDASIA) • Ensuring that product quality and manufacturing issues keep pace with speed of clinical development • Immune responses to therapeutic protein products/novel technology products: LI research-reviewers consult across the agency on these issues • Immediate hypersensitivity responses; • Abrogation of efficacy of life saving or highly effective therapeutics • Clinical deficiency syndrome due to cross reactive neutralization of endogenous protein • Immune tolerance induction

12. DTP Approved Products • Product Diversity • Wide diversity in product origin, cell substrate production systems, mechanism of action, and complexity • Mostly recombinants, some naturally derived • 80 approved products • All therapeutic proteins other than mAbs, most Ig fusion proteins and classical endocrine hormones: • Hematologic and somatic cell growth factors (eg Epo, G-CSF) • Thrombolytics and anti-thrombotics (eg tPA) • Therapeutic enzymes: intracelluar (LSDs) and extracellular targets (eg asparaginase, urate oxidase): rare diseases • Botulinum toxins: toxicity, counterfeit • Toxin conjugates • Interferons, interleukins, immunomodulatory agents • Receptor antagonists • Combination biologic/device (eg bone morphogenic proteins)

13. Products Approved by DTP 2009-2012 • Kalbitor (Ecallantide); plasma kallikrein inhibitor: LC • Xiaflex: Collagenase clostridium H: LC • Dysport (abobotulinumtoxin A): LI • Xeomin (Incobotulinumtoxin A): LI • Extavia (Interferon beta-1b): LI • Pancreaze (Pancrelipase): LC: from porcine pancreas glands • Creon (Pancrelipase): LC. “ • Zenpep (Pancrelipase): LC. “ • Pertzye (Pancrelipase) LC • Ultresa (Pancrelipase) LC • Viokace (pancrelipase) LC • Lumizyme (Alglucosidase alfa): LC-rare disease indication • VPRIV (Velaglucerase alfa): LC-rare disease indication: first plant cell based approval • Krystexxa (pegloticase; pegylated urate oxidase):LC • Belatacept (CTLA4-Ig): LI • Erwinase (asparaginase Erwinia): LC • Voraxaze (glucarpidase): LC • Elelyso (taliglucerase alpha): LC. Novel carrot cell production system • JETREA (ocriplasmin) Intravitreal Injection: for the treatment of symptomatic vitreomacular adhesion including macular hole-LC • Tbo-filgrastim LC • Albuferon: IFN-HSA fusion protein NOT APPROVED • 4 additional BLAs and NDAs reviewed but not approved

14. Ongoing BLA Approval Submissions • Metroleptin: leptin analog for Type II DM and obesity-LI • Lipefilgrastim, pegylated G-CSF-LC: neutropenia • Balugrastim, G-CSF fusion protein-LC: neutropenia • Calasparagol pegol, pegylated asparaginase: Acute Lymphocytic Leukemia • Albiglutide: type II diabetes • Vimizim, galactosamine 6 sulfatase: Morquio syndrome type A

15. Laboratory of Chemistry:Regulatory Oversight of Approved Products • Enzyme Replacement Therapies (ERT): Rare and Orphan Diseases • Lysosomal storage diseases (Gaucher, Pompe, Fabry), • Pancreatic enzyme insufficiency • Concerns • Small patient populations; • Control and enhancement of critical quality attributes important for safety and efficacy • immunogenicity • Zoonotic transmission of viruses • Products • Glucocerebrosidase (3 products) • Alpha-galactosidase A • Alpha-glucosidase (2 products, 1 approved for infants and one for adults) • Alpha-L-iduronidase • N-Acetylgalactosamine4-sulfatase • Iduronate 2-sulfatase • Pancreatic enzyme extracts (7 products) • Sacrosidase

16. Challenges in the Development of Therapeutics for Rare Diseases • Sensitivity of critical quality attributes, known to impact clinical performance, to manufacturing changes: e.g. sialic acid and mannose-6P. • Most rare disease therapeutics are complex products, with multiple moieties contributing to the mechanism of action, thus requiring multiple potency assays. Some potency assays (eg cellular uptake assays,) may be technically complex and challenging. • Given the rarity and seriousness of the diseases, clinical development is accelerated. Product quality and manufacturing consistency issues a challenge for accelerated development: • few product lots are used in the clinical trials, particularly in the pivotal clinical trial causing difficulty in establishing release and stability acceptance criteria that ensure consistent clinical performance.

17. Laboratory of Chemistry: Regulatory Oversight of Approved Products Extracellular substrate degrading enzymes: Treatment of leukemia (asparaginase), Treatment of methotrexate toxicity (carboxypeptidase) Treatment of tumor lysis and gout (urate oxidase) Dispersion of drugs in tissues/degradation of extracellular matrix (hyaluronidases) Concerns Stability of PEG-protein link Immune responses to enzyme and/or PEG Consistency of manufacturing Old legacy products, need for modernization of manufacturing processes 17

18. Laboratory of Chemistry: Regulatory Oversight of Approved Products • Hematologic growth factors: erythropoietins, granulocyte and granulocyte-macrophage colony stimulating factors • Somatic cell growth factors: bone morphogenic proteins, keratinocyte growth factors, platelet derived growth factors • Thrombolytics: tPA, TNKase • Combination products: eg BMP devices

19. Pegylation chemistry: pegylation of protein therapeutics is used to extend pharmacokinetics and may diminish immunogenicity: consultative reviews provided to DTP, DMA Oligonucleotide chemistry: to ONDQA Bioassays Guidances: Pancreatic Enzyme Products, Drug Master Files and Botanicals Laboratory of Chemistry: Regulatory Contributions Across the Center 19

20. Conclusions Strong research program needed to support optimal regulation of protein therapeutic products: IOM report, Commissioner Research program viability threatened by growing regulatory load and insufficient support Opinion/recommendations of external review committee extremely valuable in supporting the science base of the agency. 20

22. Researcher/Reviewer Model: Research Scientist and Product Expert • Product expert: scientific expertise on product manufacture, qualities, and biological activities • mechanism of action; • in vivo bioactivity and toxicities; • analytical methods, • Maintains active laboratory research program in field relevant to review area • Publishes research findings in peer reviewed, high quality journals • Undergoes site visit evaluation of program and yearly internal scientific evaluation