1. Batten Disease Accessing the Accelerated Approval Pathway with a Rare Neurologic Disease June 29-30, 2010 FDA Public Meeting “Considerations regarding the review and regulation of articles for treatment of rare diseases” Tracy VanHoutan, Board Member of the Batten Disease Support and Research Association (BDSRA)

2. Tracy VanHoutan • Father of 3 children; 2 affected by Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)-more commonly known as Batten Disease • Noah- Age 6, Laine- Age 4 (has fraternal twin, Emily) • Board member of the Batten Disease Support and Research Association (BDSRA)

3. What is Batten Disease? • Neuronal CeroidLipofuscinosis (NCL) • Autosomal recessive • Ultra Rare - affecting 2-4 births out of 100,000 • 10 different disorders with different defective genes • Children develop normally until onset age, then regress • Accumulation of waste material in the brain • Vision loss, ataxia, seizures, loss of motor function • Always fatal There is no FDA approved therapy for Batten Disease

4. Faces of Batten Disease Taylor Infantile NCL Mary Payton Late Infantile NCL Hayden Infantile NCL Jasper Late Infantile NCL Christiane Juvenile NCL Amber Juvenile NCL Sara Juvenile NCL Sandy Juvenile NCL Bridget Late Infantile NCL Daniel Late Infantile NCL

5. Diagnosis of Batten Disease? • Retinal Exam & MRI – only useful if physician recognizes signs of Batten • Skin Microscopy • Enzyme Levels • Seattle Children’s Hospital is the only testing lab in USA • Infantile and Late Infantile versions only • Gene Sequencing • Massachusetts General is the only testing lab in USA • Universal Carrier Screen using Next-Gen Sequencing • Beyond Batten Disease Foundation and National Center for Genome Resources developing inexpensive(<$500) test panel for 450+ rare childhood genetic disorders. Future Goal: Early diagnosis leads to improved outcomes for Batten children.

6. Potential Therapeutic Strategies • Gene Therapy • Phase I using AAV2 complete • Phase I screening for Rh10 underway • Stem Cell Therapy • Phase I complete • Phase II – application submitted to FDA • Enzyme Replacement Therapy • Currently under exploration • Small Molecule Therapy • Reduction of neuro-inflamation in LINCL & INCL • “Noah’s Hope” and “Taylor’s Tale” funding proof of concept studies

7. Therapeutic Development • 1 project currently under review with FDA • 2 projects currently recruiting patients • 6 projects in pre-clinical or proof-of-concept stage for Batten Disease • These project offer a very small amount of hope to parents currently with diagnosed children. • If they are delayed or not well understood at the regulatory level then we could lose another generation of Batten Disease children. • It is one thing to be sensitive to the needs of patients with rare fatal disorders • We believe people trained in genetic medicine should be making decisions on treatments for rare genetic disorders.

8. Developing Treatments Difficult disease due to neurologic problems Hard to measure neurologic decline in young children Variable rates of progression Variable degrees of reversible disease Clinical neurologic endpoints for studies are imprecise and variable in accuracy

9. Drug Development is Hampered by the Nature of this Difficult Disease Neurologic damage not likely reversible Most patients not diagnosed until they have neurologic disease Clinical endpoints may be too late to allow assessments of a drug effectively The populations are small and variable These difficulties have limited development of treatments If we have a drug that works, can we show it?

10. Accelerated Approval Regulations Designed to assist in the early approval of drugs that have a clear effect on a marker of disease Avoids the problem of waiting until patients die or in using imprecise clinical measures that may block or eliminate investment Yet only 1 genetic disease has been approved via these regulations Why?

11. Access to Accelerated Approval Regulations is needed for Battens A measure of brain injury should be sufficient to assess whether a very early stage baby is being improved Given the high morbidity and serious outcomes, clinical endpoint driven studies would be difficult to do The rarity and lack of other clinical data prevents Batten’s and other neurogenetic disorders from accessing the accelerated approval pathway Must treat before the disease has neurological effects This pathway is not available for the diseases that need it most, which cannot be what Congress intended

12. Rare and Devastating Neurogenetic Diseases like Batten Disease Need Access to Accelerated Approval Our kids have a 100 % probability of dying with Batten Disease We need to figure out how to allow markers of brain injury to be used to study new treatments in small numbers of patients Allowing access to accelerated approval will spur more investment in the difficult to study diseases like Batten Disease and many like it We need survival to be better than 0%

13. Recommendations 1. Establish a new Office of Drug Evaluation for Biochemical and Genetic Diseases • Add experienced staff with appropriate genetics expertise • Focus on disease areas not well covered today • Establish guidelines for rare and ultra-rare diseases • Improve coordination between University researchers, non-profits, private companies and NIH to assist in translating research to patients.

14. Recommendations 2. Establish protocols allowing use of surrogate endpoints, specifically, qualifying neurological endpoints that would change the dynamic of clinical trials and assistant with the development of treatments • There are no FDA approved bio-chemical end-points of neurodegeneration at this time. • Surrogate endpoints would not replace clinical outcomes, but would serve as supplemental endpoints of treatment effectiveness. • Surrogate endpoints hold great potential for improving clinical trial design for ultra-rare diseases. • Acceleration and development of new treatments for patients with no other alternatives.