1. Welcome to Workshop #5: Accelerated Approval (AA) in Rare Diseases: Review of a White Paper Proposal Emil D. Kakkis, M.D., Ph.D. President and Founder EveryLife Foundation for Rare Diseases May 15, 2013 Sofitel Hotel Washington, D.C. Lafayette Square

2. The EveryLife Foundation For Rare Diseases Formed to focus on improving the development of treatments of rare diseases in February 2009 Conducting workshops and participating in conferences to help promote scientifically sound change Supporter of ULTRA/FAST legislation in FDASIA Working toward scientifically sound change to improve the accessibility of the Accelerated Approval pathway 181 Partners+

3. Workshop Series Topics Workshop #1 Statistical analyses of rare disease studies Workshop #2Clinical evaluation of rare disease treatments Workshop #3Surrogate endpoints & accelerated approval Workshop #4Developing Policy Recommendations for Accelerated Approval Workshop #5Accelerated Approval in Rare Disease: Review of a White Paper ProposalWorkshop #5Accelerated Approval in Rare Disease: Review of a White Paper Proposal Find slides from prior workshops at www.everylifefoundation.org

4. Morning Session 8:30 - 9:00 AMREGISTRATION AND BREAKFAST Introduction 9:00 AM Welcome, Brief Review of FDASIA, Draft White Paper & Overall Workshop Goals Emil Kakkis, MD, PhD President, EveryLife Foundation for Rare Diseases Session A: Challenges in Utilizing the Accelerated Approval Pathway 9:30 AM Factors that Should Enhance Rare Disease Treatment Access to Accelerated Approval Mark Thornton, MD, PhD, President, Sarcoma Foundation of America (SFA) 9:50 AMAssessing Benefit/Risk of Potential Treatments by Patients and Patient Groups Pat Furlong, President & CEO, Parent Project Muscular Dystrophy 10:10 AMChallenges in Qualifying Surrogates: FDA Perspective Marc Walton, MD, PhD Office of Translational Sciences, CDER, FDA 10:40 AMDISCUSSION: Maximizing Reasonable Access to Accelerated Approval 11:00 AMBREAK

5. Can we do better developing treatments? Sly Disease has been successfully treated in animals but no children have ever been treated 5

6. The challenges for AA in Rare Diseases Challenges in qualifying a surrogate to be “reasonably likely to predict clinical benefit” Lack of prior clinical outcome & treatment data Limited prior clinical studies or natural history Difficult clinical biology not easily studied Yet science and medicine may be solid and clear Key question: How do we practically qualify biomarkers for use with little prior clinical experience?

7. In FDASIA (PDUFA V) US Congress Legislation: H.R. 4132: FAST Introduced By Rep. Stearns and Townes Better access to Accelerated Approval Pathway 7 “Considerations. – In developing the guidance.... the Secretary shall consider.... for drugs designated for a rare disease or condition under section 526 of the Federal, Food, Drug, and Cosmetic Act; and (2) how to incorporate novel approaches to the review of surrogate endpoints based on pathophysiologic and pharmacologic evidence in such guidance, especially in instances where the low prevalence of a disease renders the existence or collection of other types of data unlikely or impractical.”

8. At Workshop #4, created the plan Draft set of criteria were considered A working group was formed White paper to consolidate recommendations for AA under FDASIA Work Shop #5 Key Goal Review a proposed White Paper on recommendations for access and qualification considertions for AA Workshop #5: Accel Approval in Rare Diseases Review of a White Paper Proposal

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10. White Paper on AA in Rare Diseases Working Group Industry and Foundations 10 Marc BoutinNational Health Council SusanBoyntonShire HGT MladenBozicShire HGT GeraldCoxGenzyme, A Sanofi Company PatFurlongParent Project MD MarkHayesSynageva Emil KakkisEveryLife Foundation for Rare Diseases CoriLeonardUltragenyx Pharmaceutical RachelMackVertex Pharmaceuticals Inc. MaryO'DonovanBioMarin MayOrfaliPfizer MarkThorntonSarcoma Foundation of America JackWeetSeaside Therapeutics

11. Surrogate endpoint considerations Prentice criteria: A set of mathematical criteria on how one variable represents another: not biological Fleming (2005) reworked to focus on biological pathway issues –Direct measures versus parallel measures –Alternative unmeasured adverse pathways –Tiers of surrogates proposed Fleming concepts valid but not experimentally defined Need a practical implementation of concepts 11

12. Developing a scientific framework for for qualification of a biomarker for AA Breakdown the surrogate endpoint analysis into individual specific scientific considerations –Disease, Drug, Biomarker Better understanding of science at each level provides greater support for predictive value Support the underlying science –Preclinical data and clinical supportive information Find the balance of data that meets the standard 12 “Reasonably likely to predict clinical benefit”

13. White Paper: Improving Scientifically Sound Access to the AA Pathway Reviews the criteria for rare disease access –What factors should be considered in flexibility for AA as a pathway? Defines Disease, Drug, BioMarker characteristics that enhance predictability Defines preclinical and clinical data to support the qualification Discusses Clinical Trial Design and Confirmatory studies 13

14. I.Introduction II.Background II.Considerations regarding the benefit-risk assessment IV. Scientific considerations for the qualification of biomarkers V.Summary considerations for qualification of a disease/drug/biomarker VI.Clinical trial design considerations VII.Conclusions VIII.References White Paper Table of Contents 14

15. Accelerated approval standard: Finding the balance in Benefit/risk “A surrogate endpoint or clinical endpoint earlier than irreversible morbidity and mortality” that is “reasonably likely to predict clinical benefit” What should set the standard for benefit-risk in rare diseases? –The disease matters: –Rarity, severity, biology, unmet need –Science behind the disease, endpoint and drug mechanism 15

16. 1) Benefit-Risk Considerations Assessment should be evaluate the specific context of the disease, its rarity and other factors. Extremely high unmet medical need Extreme rarity Absence of any prior clinical study or clinical data Slow or irreversible disease Significant delay between the onset of irreversible disease and clinical diagnosis Lack of readily measurable clinical endpoints due to unusual clinical disease manifestations 16

17. 2) Scientific Basis Considerations for a Disease/Drug/Biomarker Group Data in hand before extensive preclinical/clinical research Disease considerations Drug considerations Biomarkers considerations 17

18. Scientific Context of Use for a Disease/Drug/Biomarker Set A biomarker must be viewed in its context: –A disease mechanism connected to a certain drug action, leading to a biomarker result The scientific relationship is critical to value as a surrogate The group must be considered linked Changing the drug mechanism or biomarker might not provide the same predictive value 18

19. 19 MPS Disease/Endpoint/Drug Considerations DISEASE BIOMARKER DRUG

20. Scientific Data Considerations for a Disease/Drug/Biomarker Group Data developed from preclinical & clinical research Preclinical research –Specific research data to support the relationships/validity of insights Clinical data to support qualification –Cross-sectional survey –Natural history data –Other data 20

21. 3) Clinical Study Data for Approval and for Post-marketing Confirmation Adequate well-controlled studies Pivotal study designs –Efficacy/biomarker –Safety Placebo control –Alternative use of blinded evaluation –Natural history comparison 21

22. 4) Post-marketing Confirmation Requirements and challenges Confirmatory study designs –Complexities –Alternative designs Placebo and natural history controls Withdrawal 22

23. Making AA practically assessable when it is the best choice for development Predictable set of issues to collect and present at a pre-IND meeting –Need the opportunity early in development Patient benefit-risk input via a sophisticated quality survey at the start –Provides the data on right benefit-risk choice Early AA accessibility means more investment in more treatments

24. Goals of today’s workshop Discuss the elements of the guidance –Benefit/risk, Scientific qualification, Studies for approval, Confirmatory studies –Identify major omissions or issues that need to be resolved –Collect the major unresolved challenges for qualification Provide examples for inclusion in the white paper Build consensus of an improved document 24

25. Morning Session 8:30 - 9:00 AMREGISTRATION AND BREAKFAST Introduction 9:00 AM Welcome, Brief Review of FDASIA, Draft White Paper & Overall Workshop Goals Emil Kakkis, MD, PhD President, EveryLife Foundation for Rare Diseases Session A: Challenges in Utilizing the Accelerated Approval Pathway 9:30 AM Factors that Should Enhance Rare Disease Treatment Access to Accelerated Approval Mark Thornton, MD, PhD, President, Sarcoma Foundation of America (SFA) 9:50 AMAssessing Benefit/Risk of Potential Treatments by Patients and Patient Groups Pat Furlong, President & CEO, Parent Project Muscular Dystrophy 10:10 AMChallenges in Qualifying Surrogates: FDA Perspective Marc Walton, MD, PhD Office of Translational Sciences, CDER, FDA 10:40 AMDISCUSSION: Maximizing Reasonable Access to Accelerated Approval 11:00 AMBREAK

26. Session A: Presentations

27. Session A : Benefit-Risk Discussion What are the key issues to be considered that impact access to AA? –Degree of Rarity –Severity, unmet medical need –Difficult biology like brain, bone? –Difficulty conducting a traditional trial?

28. Mid-Morning Break

29. Session B: Qualification of Biomarkers for a Specific Disease and Drug 11:15 AM Scientific Considerations Regarding the Disease, the Drug and its Action, and the Biomarker Emil Kakkis, MD, PhD President, EveryLife Foundation for Rare Diseases 11:35 AMPreclinical Data to Support Biomarker Qualification Gerald Cox, MD, PhD Senior Director, Genzyme Corporation 11:55 AM Cross-Sectional Surveys and Natural History Studies to Support Clinical Interpretation P.K. Tandon, PhD Sr. VP Global Biomedical Data Sciences & Informatics, Genzyme Corporation 12:15 PMDISCUSSION: Qualification Criteria 12:45 - 1:15 PMLUNCH

30. Scientific Considerations Regarding the Disease, the Drug and the Biomarker Emil D. Kakkis, M.D., Ph.D. President, EveryLife Foundation for Rare Diseases CEO, Ultragenyx Pharmaceutical Inc.

31. Scientific Framework for AA Considerations for Qualifying a Biomarker for Use A set of considerations consisting of specific scientific data that support the interpretation of predictive value –Disease, Drug and BioMarker Data support the relationship between the disease mechanism, drug action and biomarker biology Not a checklist, but an outline of data that collectively improve predictive value

32. The value of providing a scientific framework for qualification Guides early research toward collecting the informative data Provides sponsors a common framework for evaluating opportunities that may depend on AA for investment Standardizes considerations during regulatory review and development Does not substitute for good judgment –Supports good decisions

33. Summary Considerations for Qualification of a Disease/Drug/BioMarker Set for Accelerated Approval A. DISEASE CONSIDERATIONS B. DRUG CONSIDERATIONS C. BIOMARKER CONSIDERATIONS D. PRECLINICAL DATA CONSIDERATIONS E. CLINICAL DATA CONSIDERATIONS FOR BIOMARKER QUALIFICATION

34. Disease Considerations Cause is clear –E.g., single gene, specific biology –Single known pathophysiologic cause Pathophysiologic pathway is understood No known adverse pathways that cannot be measured The more known is about the disease and how it causes clinical problems, the more confidence exists in the direct link to the drug and the biomarker measuring the disease

35. The Disease is Clear: Phe in PKU PAH Enz. Defective In Liver [ Blood Phe] Blood-Brain Barrier Brain injury High Phe level 59 uM 360-2500 uM 10x to 50x Measure Blood Phe Level Degree of long-term Brain Injury Compartment Question BH4 Increases PAH in Liver [ Blood Phe] Brain injury reduced due to lower Phe level BBB

36. Drug Considerations The drug’s structure and identity are clear The mechanism of action of the drug is direct and understood. The pharmacologic action and specific function of the drug can be demonstrated Studies of the drug in models demonstrate relevant absorption, distribution, metabolism and excretion (ADME). There appear to be no significant off-target alternative adverse activities of the drug

37. Replacing a missing protein with a recombinant version of the protein Factor VIII deficiency Lysosomal enzyme replacement therapy  1-antitrypsin deficiency

38. rhIDU is targeted for uptake Reaches intracellular compartment untreated treated Enzyme replacement therapy (ERT) for MPS 1 Enzyme reaches target and delivered to site of action nucleus Lysosome Filled with MPS The enzyme

39. BioMarker Considerations Directly in line within the pathophysiological map Sampling compartment predicts the disease compartment Assay is sensitive and specific with a sufficient range. Reasonable biologic stability. Assay methodology should be validated Accepted clinical physiologic measures may be considered predictive if they measure major clinical problems in the rare disease. Measuring a disease process, reliably and accurately with a biomarker directly line of the disease process.

40. Biomarkers for Brain Disease Cerebrospinal fluid and the Brain in LSD’s Does it reflect brain biochemistry/biology? Will CSF Samples Reflect the brain?

41. Pathophysiologic Map: MPS I & Brain GAG IDUA Deficient In Cells & LSD Cell Leakage Rupture release Heparan sulfate Diffusion via Tissue fluid to CSF ERT Diffuses, Replaces Def [ Cell Rupture] Clinical Outcome Improved Meningeal storage Microglial Neuronal Glial Storage in neurons, glia Microglia and meninges Multiple cell type storage Cord Compression Inflammation Neuronal loss Myelination abn l Biomarker Clinical Outcome Compartment: Does Urinary GAG reflect tissue storage and outcome? [ Cell storage] ? Heparan Accumulation Treatment

42. Dynamic Range of a Biomarker pGAG specific to abnormal GAG has larger dynamic range and is more sensitive to treatment change Total GAG pGAG Data: Dickson Laboratory work using Zacharon Pharmaceuticals SensiPro Assay Total GAG pGAG RANGE

43. Compartment is important IT ERT Normalizes Brain pGAG levels Reflected by CSF pGAG levels

44. CSF samples do reflect the brain compartment metabolically Preclinica l Intrathecal enzyme replacement provides the therapeutic predictive insight MPS I canines Sanfilippo A dogs and mice Neuronal ceroid lipofuscinosis 2 mouse and dogs MLD studies Adrenoleukodystrophy How will be successfully develop treatments for neuronal storage diseases?

45. 45 Early versus Late Markers in the Pathway Map “Early” disease markers closest to source of disease, least prone to variation or unknown influences “Late” pathophysiology markers closes to clinical disease and outcome but potentially more unknown influences

46. Preclinical data on the disease/drug action 46 Clinical data to support the qualification of the biomarker Presentations

47. Summary of Preclinical and Clinical Data Preclinical Dose-response curve well defined –Subtherapeutic and therapeutic doses Dynamic response: start and remove Rx –Sensitivity to mitigating effects (Ab response) Strong correlation to pathophysiologic effect No substantial evidence of an alternative adverse pathway activated by Rx

48. Clinical data considerations in absence of clinical outcome information Natural history studies are best but hard to complete: Time and patient numbers Cross-sectional survey in untreated patients at different stages of disease severity –Develop correlation of marker with severity –Can cover decades of disease progression Comparable disease states with homologous markers do show association with clinical benefit in similar context of use

49. Section B : Scientific Framework for Qualification Qualification criteria Are there other factors in the science of a disease/drug/biomarker set that should be considered? –Diseases are complex: can we readily define clarity of cause? –Drug mechanism relative to disease is important: is defining action critical to qualifying a drug or just supporrtive? –How direct is direct in biomarkers? –How hard is it to define alternative adverse pathways Supporting qualification with clinical data –What are the risks or issues with using cross-sectional human data can be used to support biomarker qualification? –Natural history data use in support of surrogate meaning.

50. Lunch Break

51. Afternoon Session Session C: Clinical Studies to Support Accelerated Approval 1:15 PMPhase 3 Clinical Studies for Accelerated Approval Emil Kakkis, MD, PhD President, EveryLife Foundation for Rare Diseases 1:35 AMChallenges in Utilizing Accelerated Approval Robert Temple, MD Deputy Director for Clinical Science, FDA 1:55 PM DISCUSSION: Clinical Data for Surrogate Qualification and Clinical Studies for Accelerated Approval

52. Pivotal Study Trial Design: Concepts for studies using a primary surrogate marker endpoint Randomized, controlled studies are preferred when feasible and appropriate – Should be conducted in most situations An adequate assessment of safety is required – Smaller size studies still requires sufficient “n” Accelerated approval should not require internal validation of the biomarker – Clinical endpoint was not feasible in first place

53. Randomized, placebo-controlled studies: More plausible using a biomarker primary Power often increased, allow small randomized controlled studies Need to assess safety optimally with placebo control when possible Can still conduct valid clinical assessments if underpowered Risk of conflict between biomarker and clinical results

54. Alternative Clinical Study Designs When reasonable and feasible, should do randomized controlled studies What about when not possible? –Too small, variable population –Ethical issues Randomized controlled, without placebo Cross over designs, single, double, N=1 Blinded observations but open label design

55. Blinded Observations in Open Label Studies Ethical or challenging clinical situations Example: late infantile Batten’s Disease Severe neurologic disease, onset 2-5 yrs Cannot ethically conduct intraventricular ERT therapy using placebo Study of a neurologic biomarker and imaging, neurologic scoring –Use blinded specimens for the biomarker –Blind and randomize sequence of MRI –Scoring behaviors by video if possible 55

56. 56 12 subjects randomized to one of four (A-D) groups to either start on 2 mg/kg UX003 (A) or start on placebo (B-D) and cross over to 2 mg/kg UX003 in blinded manner at different pre-defined timepoints Subjects and observers do not know when subjects cross onto drug Rx Dosed every other week for 48 weeks. All groups receive a minimum of 24 weeks of 2 mg/kg UX003 therapy UX003-CL201: Blinded Start Design

57. Natural history control strategies Extremely challenging to provide comparable non-parallel control –Variations in patients, ancillary treatment, differences in observation Need to control patient comparability Difficult to use in pre-marketing setting and requires consultation and preparation

58. Clinical study section in the White Paper Focused on high-level recommendations Not intended to provide specific study design recommendations Supporting the need for quality study designs to maximize information Safety evaluation still needed Consideration for how confirmation of clinical benefit will occur is important

59. Session D: Post-Marketing Confirmatory Studies of Clinical Benefit 2:20 PMPost-Marketing Confirmatory Studies Susan Boynton Vice President, Global Regulatory Affairs, Shire Mary O'Donovan Senior Director, Regulatory Affairs and Policy, BioMarin 2:50 PMDISCUSSION: How Do We Accurately Confirm Clinical Benefit Post-Marketing? 3:20 PMSummary and Final Discussion, Steps Going Forward and Closing Remarks Emil Kakkis, MD, PhD President, EveryLife Foundation for Rare Diseases 3:45 PMEND OF WORKSHOP

60. The End Thanks to all the Sponsors EveryLife Foundation For Rare Diseases