Creating action with information: The Rare Disease Community

Cary O. Harding, MDDepartment of Molecular & Medical Genetics

Disclosures

• BioMarin Corporation– Funds for participation in clinical trials

• Sapropterin dihydrochloride• rAvPAL-PEG

• National PKU Alliance– Funds for PKU gene therapy research

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.

TEAMWORK• http://photos.presstelegram.com/2012/07/ph

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Outline

• Future treatments• Current therapy• Legislative and regulatory issues

Future therapy

• rAvPAL-PEG• Novel large neutral amino acid therapies• Probiotic therapy• Hepatocyte transplantation• Gene therapy

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

rAvPAL-PEG Phase III

• More clinical sites• Proof of efficacy• Investigate self-administration• Evaluate side effects

– Skin rashes– Joint swelling

• Monitor for adverse events

Timeline and funding

• First published report – 1999• Phase 3 study – 2013• FDA approval - ?2016• Funding

– Government grant– Private foundation money– Pharmaceutical company

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

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

Status of current therapy

• ? Nutritional adequacy of current dietary therapy– Intact protein vs. free amino acids– Micronutrients– Bone effects

• Neuropsychologic outcomes• Pathophysiology of PKU

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

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

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

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

Newborn Screening Translational Research Network

• National database• Long term outcome of all disorders detected

by newborn screening

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

Conclusions

• The future of PKU treatment and research is promising!

• Collaboration essential– Clinical centers– Government agencies– Private philanthropic foundations– Pharmaceutical companies– Patient advocacy organizations

The critical catalyst?

YOU!

NPKUA