1. Creating action with information: The Rare Disease Community Cary O. Harding, MD Department of Molecular & Medical Genetics

2. Disclosures BioMarin Corporation –Funds for participation in clinical trials Sapropterin dihydrochloride rAvPAL-PEG National PKU Alliance –Funds for PKU gene therapy research

3. Take home messages The future of PKU research and treatment is very promising. The barriers to progress are shared by many rare disorders. Collaborative efforts are critical to maintaining progress. Patient advocacy groups (eg. NPKUA) have immense impact.

4. TEAMWORK http://photos.presstelegram.com/2012/07/ph otos-cycling-at-the-london-2012-olympics- july-28/ - 6http://photos.presstelegram.com/2012/07/ph otos-cycling-at-the-london-2012-olympics- july-28/ - 6

5. Outline Future treatments Current therapy Legislative and regulatory issues

6. Future therapy rAvPAL-PEG Novel large neutral amino acid therapies Probiotic therapy Hepatocyte transplantation Gene therapy

7. Collaboration is essential! rAvPAL-PEG –Proof of concept in academic center McGill University –Further refinement in private foundation lab Scripps Institute –Preclinical validation in an academic center with pharmaceutical company support University of Florida –Clinical trials in multiple centers BioMarin

8. rAvPAL-PEG Phase III More clinical sites Proof of efficacy Investigate self-administration Evaluate side effects –Skin rashes –Joint swelling Monitor for adverse events

9. Timeline and funding First published report – 1999 Phase 3 study – 2013 FDA approval - ?2016 Funding –Government grant –Private foundation money –Pharmaceutical company

10. Gene therapy Preclinical studies –Develop preclinical vector –Proof of concept –Refine vector –Investigational new drug application –Production of vector in GMP facility –Large scale pharmacologic studies First in human Phase 1 trial

11. Acknowledgements Grompe Lab - OHSU –Markus Grompe –Nick Morcinek –Zhongya Wang –Laura Roy Koeberl lab – Duke –Dwight Koeberl –Andy Bird Thöny lab – Zurich –Beat Thöny –Hiu Man Viecelli –Alex Rebuffat Harding lab – OHSU –Shelley Winn –Katie Cobb –Kevin Watanabe-Smith –Lindsey Stetson –Baoyu Lin –Gloria Baca –Kelly Hamman Funding –NPKUA –NIH

12. Status of current therapy ? Nutritional adequacy of current dietary therapy –Intact protein vs. free amino acids –Micronutrients –Bone effects Neuropsychologic outcomes Pathophysiology of PKU

14. Needed investigations Animal models –How does Phe affect the brain? –What dietary variables affect physical outcome? Human investigations –Neuropsychologic and imaging studies –Effects of pharmacologic therapy –Long term follow up

15. Recent NIH/FDA efforts National Center for Advancing Translational Studies (NCATS) –Office of Rare Diseases Research FDA Office of Orphan Products Development Meetings in 2011 and 2012 –Further research on medical foods –Research needs specifically for PKU

16. Rare Disorders Consortia NIH funded with additional philanthropy Multisite collaborative clinical research –Longitudinal natural history studies –Prospective research studies Multiple collaborators –Academic centers –NIH –Patient advocacy groups –Pharmaceutical companies

17. Urea Cycle Disorders Consortium 16 centers – Two in Europe Longitudinal study –Effectiveness of current therapy –Long term outcomes Liver disease Liver tumors Novel pharmaceutical therapies NUCDF intimately involved

18. Newborn Screening Translational Research Network National database Long term outcome of all disorders detected by newborn screening

19. Legislative efforts Uniform availability and funding for medical foods –Some states have legislative mandates Medical Foods Equity Act Insurance exchanges under Obamacare –Defining minimal benefit package for participating insurance plans

20. Conclusions The future of PKU treatment and research is promising! Collaboration essential –Clinical centers –Government agencies –Private philanthropic foundations –Pharmaceutical companies –Patient advocacy organizations

21. The critical catalyst? YOU! NPKUA