RARE DISEASE WORKSHOP SERIES

Improving the Clinical Development Process

Workshop 3

Use of Surrogate Endpoints in Rare Disease Treatment Development
November 8-9, 2011
Sofitel Hotel Washington, DC Lafayette Square

AGENDA

Day 1 – Morning

Introduction to the Challenges of Using Biomarkers as Surrogate Endpoints in Clinical Development
8:00 am	Welcome and Opening Remarks Emil Kakkis, M.D., Ph.D., President, EveryLife Foundation for Rare Diseases
8:10 am	Surrogate markers in clinical development Thomas Fleming, Ph.D., Prof. of Biostatistics and Statistics, University of Washington
8:40 am	Biomarkers as Surrogates: Appraising Persuasiveness Marc K. Walton, M.D., Ph.D., Associate Director for Translational Medicine, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration
9:10 am	The history and challenges of biochemical genetics markers and the development of qualification criteria for surrogate endpoints intended for accelerated approval Emil Kakkis, M.D., Ph.D., President, EveryLife Foundation for Rare Diseases
9:30 am	Discussion
Blood levels of neurotoxic compounds
9:40 am	Surrogate markers in the evaluation of therapies for hyperammonemia in urea cycle disorders Mendel Tuchman M.D., Chief Research Officer, Children's National Medical Center Scientific Director, Children's Research Institute, Professor of Pediatrics, Biochemistry & Molecular Biology
9:55 am	The development of phenylalanine blood levels as a surrogate endpoint in phenylketonuria Emil Kakkis, M.D., Ph.D., President and CEO, Ultragenyx Pharmaceutical
10:10 am	Discussion
Urinary substrate excretion in the lysosomal storage disorders and other metabolic diseases
10:40 am	Urinary Oxalate in Primary Hyperoxaluria Pontus Larsson, M.Sc., Biostatistician, OxThera AB
10:55 am	GL-3: a urinary biomarker in Fabry disease? Pol Boudes, M.D., Chief Medical Officer, Amicus Therapeutics Inc.
11:10 am	Urinary glucose tetrasaccharide biomarker for Pompe disease Sarah Young, PhD, FACMG, Assistant Lab Director, Duke Hospital Biochemical Genetics Lab
11:25 am	Urinary GAG as a biomarker in MPS disorders Emil Kakkis, M.D., Ph.D., President and CEO, Ultragenyx Pharmaceutical
11:40 am	Discussion

Day 1 – Afternoon

Special methods for assessing anatomy or function

12:50 pm	Electrical impedance myography as a biomarker in neuromuscular disorders Seward B. Rutkove, M.D., Chief, Division of Neuromuscular Disease, Department of Neurology, Associate Professor of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center
1:05 pm	Advanced neuroimaging methods for assessing brain anatomy, biochemistry and function for urea cycle disorders Andrea Gropman, M.D., Associate Professor, Neurology and Pediatrics, The George Washington University of the Health Sciences, Attending in Neurology, Children's National Medical Center
1:20 pm	X-linked Adrenoleukodystrophy: rationale and current assessment of markers to track progression Kathleen M. Zackowski, Ph.D., O.T.R., Assistant professor, Department of Physical Medicine and Rehabilitation, Kennedy Krieger Institute and the Johns Hopkins University School of Medicine
1:35 pm	The Development and Validation of a Radiographic Endpoint for Hypophosphatasia Alison Skrinar, Ph.D., Senior Director, Clinical Research & Regulatory Affairs, Enobia Pharma
1:50 pm	Discussion
Inflammatory or disease pathology markers in lysosomal diseases
2:00 pm	Chitotriosidase assay, surrogate endpoint in Gaucher Disease Mariëtte van der Velden, MSc, General Manager, Amdix BV
2:15 pm	The use of pathology surrogate markers in Fabry Disease Beth L. Thurberg, M.D., Ph.D., Vice President of Pathology, Genzyme Corporation
2:30 pm	Discussion
Spinal fluid storage markers and spinal fluid brain injury markers for disorders of the CNS
3:00 Pm	Spinal Fluid Substrate Markers in MPS I Agnes Chen, M. D., Assistant Clinical Professor of Pediatrics and Neurology, David Geffen School of Medicine at UCLA, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
3:15 Pm	Is CSF GM2 a Surrogate Marker for the GM2 Gangliosidoses? Shripad S. Bhagwat, Ph.D., Chief Scientific Officer, Zacharon Pharmaceuticals
3:30 Pm	A prospective natural history study of MPSIIIA: baseline data and preliminary CSF biomarker identification Patrick Haslett, M.D., Medical Director, Translational Medicine, Shire Human Genetic Therapies
3:45 Pm	CSF substrate markers as predictors of CNS outcome Emil Kakkis, M.D., Ph.D., President and CEO, Ultragenyx Pharmaceutical
4:00 Pm	Discussion
Histologic and serum markers to assess protein expression levels or injury for Duchenne Muscular Dystrophy
4:10 Pm	Opportunities and Challenges for Muscle Dystrophin as a Biomarker to Evaluate Treatments for DMD John Babiak, Ph.D., Sr. Vice President, Drug Discovery Technologies, PTC Therapeutics
4:25 Pm	Semi-quantitative immunohistochemistry of dystrophin expression as a surrogate marker in DMD Diane Frank, Ph.D., Director, Discovery Research Biology, AVI BioPharma
4:40 Pm	Discussion
4:50 Pm	Wrap-up of Day 1
5:00 Pm	End of Day 1

Day 2 – Morning
8:00 am	Brief Review of Day 1 and Plan for Day 2 Emil Kakkis, M.D., Ph.D., President, EveryLife Foundation for Rare Diseases

8:05 am	The utility of muscle strength as a surrogate for change in function in neuromuscular disease Linda Pax Lowes, P.T., Ph.D., Research Coordinator for Clinical Therapies and Investigator in the Research Institute Center for Gene Therapy, Nationwide Children's Hospital
8:25 am	Intermediate physiologic measures of clinical function: Surrogate or clinically meaningful? Emil Kakkis, M.D., Ph.D., President, EveryLife Foundation for Rare Diseases
8:35 am	Discussion: Interpretation of data from Day 1: Biomarkers in Rare Diseases and what have we learned Are biomarkers in rare genetic diseases more likely to be predictive of clinical disease given their closer and more direct relationship to the disease and mechanisms? Identify key points regarding what works for predictive biomarkers. What does not work and what can we use to filter/test proposed biomarkers? What checks should be established?
9:30 am	Discussion: Establish qualification criteria for biomarkers Do the proposed criteria help drive scientifically sound qualifiable surrogates? How do the proposed criteria work and what is missing or not adequate? Is there a way to incorporate our experiences into credible starting place for a guidance?
10:30 am	Discussion: Verification of clinical benefit post approval How do we finish the development and obtain the right confirmatory data to establish clinical efficacy? What is the critical information that might be derived from similar disease states to the one being studied that might support the qualification of an evaluative tool as reasonable for a rare disease? What are the best practices needed in pre-approval development to allow effective post-approval confirmation?
11:25 am	Closing remarks and resolutions for actions going forward: Turning talk into guidance.
11:30 am	End of workshop

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