Nathan’s Battle Grant Request Proposal

Gene Transfer Therapy Executive Summary

Nathan’s Battle Foundation was established to aid in the development of therapies for Late Infantile Batten Disease. Late infantile batten disease is a fatal, rare degenerative neurological disease. This disease takes no mercy on its young victims. Children typically have seizures, loss of motor control, as well as the ability to think and reason coherently and end up bedridden requiring a feeding tube for nourishment with the average life expectancy of ten years of age.

The beginning of Nathan’s Battle Foundation came about when Nathan, the son of Phil and Tricia Milto, was diagnosed with Late Infantile Batten Disease. Nathan’s parents identified a need to spearhead therapeutic research for this devastating disorder. The Milto’s discovered that very little scientific research was being performed in this area, thus the need for such a foundation. The Nathan’s Battle Foundation was established in 1999 and formally received Non-For-Profit determination in May of 2000.

For the Milto’s this fight became increasingly more important as their younger son PJ was also diagnosed with this fatal disease. Their futures as well as the future of over 500 other children depend on this crucial research, research that is within reach if given the financial backing.

There has been many steps taken to accomplish their mission. Joined with Cornell University their mission is close at hand. Promising therapeutic approaches have been developed. Included in these approaches is gene transfer therapy. This therapy would be a long-term cure for Late Infantile Batten Disease. Nathan’s Battle Foundation and Cornell University joined together in developing a five-stage process that would ultimately complete a clinical trail for gene transfer therapy. Stage one, defining the scope, plan and timeline, has been completed. In addition, stage two consisting of creating specific plans and timelines has also been accomplished. However, the remaining three stages required funding that has not been established at this time.

This funding will provide Nathan’s Battle Foundation with the ability to complete the main objective of a clinical trail through the remaining three stages. The third stage of this process is where there is vector production and development of a clinical plan. Vector testing / validation and regulatory process will be completed in the fourth stage. And, the remaining task of clinical trail will be the final stage. These stages are demanding and crucial at the same time. Without funding for these stages of the gene transfer therapy Nathan, PJ and many others will be left with no hope for the future and no chances of a cure during their short lifetimes.

Nathan’s battle is a battle that can and must be won for the sake of Nathan, PJ and the many other children who are innocent victims of this fatal disease.

Total Dollar Amount Needed: $2,100,000 Project Duration date: Stage Three 5/15/01 – 6/28/02

Stage Four 7/02/01 – 8/04/03Stage Five 8/05/03

Need Statement

Nathan is a five-year-old who is loosing his function, and it is for him that Nathan’s Battle Foundation was established. Nathan has gone from a child who was active to a child who can no longer accomplish basic daily tasks. Since his diagnosis he has lost his eyesight and his cognitive and communication skills have deteriorated. And, he is not alone in his suffering, there are over 500 other children including his younger brother PJ who have been diagnosed with the fatal Late Infantile Battens Disease.

Batten disease is one of a family of diseases called neuronal ceroid lipofuscinoses (or NCL’s) that attack the metabolic properties of the nervous system. When the metabolic systems are compromised, the cells of the body cannot properly recycle their waste. Without that recycling process, the cells and the body breaks down. Over time, affected children suffer mental impairment, seizures, and loss of sight and motor skills. Batten disease is always fatal. Late Infantile Batten disease, also known as CLN2, affects 1 in 250,000 new births. When all the 40 similar diseases that can benefit from this research are added up, the rate of incidents drops to less than 1 in 6,700.

However, these children diagnosed with CLN 2 have hope for their future with your help. There is a potential therapy that may enable these children to live a long fulfilling life. Gene Transfer Therapy is a promising approach to Late Infantile Battens Disease. Gene therapy using the Adeno-associated virus (AAV) has been associated to be effective at reducing lysosomal storage in many tissues including neurons of the central nervous system in a murine model of a lysosomal storage disease. In addition, the use of AAV as a gene transfer vector is based on over 15 years of basic research.

Nathan’s Battle Foundation has initiated and recruited key organizations, institutions, and renowned research scientist as well as large and small companies in their fight. Their united efforts have proven successful in initiating the process and beginning the vital stages. However, without key funding their efforts will come to an abrupt halt.

In addition, Nathan’s Battle Foundation has developed a working relationship with the Institute of Genetic Medicine Weill Medical College of Cornell University which can provided clinical trails for this therapy. They have already completed the groundwork and now they need funding to gather the pre-trial data and to initiate the clinical trails. Their work already accomplished will serve as a base. Here the scope has been defined, timelines have been determined and plans have been developed. Cornell University has allowed Nathan’s Battle Foundation to pay $100,000 per month because of the tremendous promise the project has. Gene therapy has been proven to be effective in treating similar disorders by getting a functioning gene back into the central nervous system to produce the missing enzyme and curing the disease.

Results of gene transfer therapy have far-reaching potential. Once proven successful, there are hundreds of children that will be given a renewed chance at life. And, the information learned from these trails will provide a basis for other gene therapies for the future. Thus providing vital information for over 40 other rare diseases. Therefore, this clinical trail could have an impact in over 50,000 people’s lives. This project can advance medical science by being one of the first gene therapy projects into the central nervous system. It is the cutting edge in medical science and has great potential for shaping the future of medicine.

Objectives

As a result of this award the five-stage process developed by Cornell University will be completed. Since the first two stages are completed the funding will assist in completing the remaining three stages which are included in the following objectives:

Objective #1. Completion of proposed stage three. This stage will consist of vector and analytic development as well as pre-clinical studies for distribution and expression. And, the production of GMP grade vectors and the completion of a clinical protocol.

Objective #2. Completion of proposed stage four. This stage will consist of testing and validating the clinical grade vectors, obtaining IRB, IBC, and RAC approvals, writing an IND application, obtaining FDA approval and initiating clinical trails.

Objective #3. Completion of proposed stage five. This stage will consist of the initiation and completion of clinical trails.

Objective #4. Generate a model for other gene therapy clinical trails.

Proposed Method/ Procedure

Clinical trails are time consuming and financially expensive. In addition they require the knowledge of experts and the scientific know how to develop appropriate trials that maintain within guidelines. Nathan’s Battle has established a working relationship to obtain these needs of the clinical trail. Cornell University has established what they would be able to accomplish to assist in this clinical trail. They have explained out the various procedures that are necessary and the methods in which these procedures will be implemented. The stages remaining to be completed and the procedures in which they will be carried out are broken down into tasks below and noted by their purpose, time frame and cost.

Purpose/ step needed Time frame Costs

Vector and analytic development 5/ 01 – 11/01 $300,000

Pre-clinical studies for distribution 5/01 – 1/02 $500,000and expression

GMP vector process development 5/01 – 5/02 $300,000

Clinical protocol development 7/01 – 6/02 $500,000

Toxicology studies 8/02 – 2/03 Previously included

FDA submission 6/03 – 8/03 Previously included

Clinical Trials initiation 8/03 – unknown $500,000

Estimated total costs: $2,100,000

It is important to note that in regards to the FDA submission of this process the investigational new drug submission for AAV gene therapy for CLN 1 and CLN 2 is being designated as a compassionate use drug. This designation under the Orphan Drug Act will allow for fast tracking priority review expediting the process. Also, under the Orphan Drug Act, the FDA is willing to work with this trial on the necessary requirements. Targeting the NCL disorders is a low risk, high reward situation.

Once the project is completed the first phases of a clinical trial are completed, we will have proven the efficacy of the drug for a biotech company to manufacture. Negotiations with a biotech company (Genzyme) have been established to commercialize the drug to make it available to the community (see the attached Non-For-Profit Therapy Development Model Diagram).

The gene therapy project can be easily evaluated by reviewing the progress against the tasks and time frames defined in the work plan. Following the work plan timeline closely will be a major emphasis. We are fighting time with this disease so the project will be measured regularly to facilitate the timely success.

Budget

The current total estimated budget for the LINCL gene therapy project is $2.1million dollars. The project costs are derived from the project work plan prepared by the Institute of Genetic Medicine Weill Medical College of Cornell University (see appendix for copy of work plan). The work plan specifies tasks and milestones associated with the project. These tasks will require professional resources and associated supplies to develop the drug. These funds will be used to accomplish major project milestone, including the first phase of a life saving clinical trial on humans. The major project milestones involve: the manufacturing of the drug, remaining necessary pre-clinical testing, clinical protocol development, regulatory approval process, and human administration in the first phase of the clinical trial. The costs associated with each milestone are inclusive of scientific materials, laboratory specimens, equipment, professional services, and indirect cost. Cornell University charges a reduced rate for indirect charges for Non-For-Profit organizations of 25%.

The Nathan’s Battle Foundation will contribute all personnel time at no charge to the project. Copies of the project budget from the first two stages of the LINCL project are included in the appendix.

BudgetedProject Milestone Expenses Amount

Vector and analytic development $300,000Initial vector construction Develop analytical methods

Pre-clinical Studies $500,000Distribution StudiesExpression StudiesToxicology studies

GMP clinical grade vector process development $300,000GMP Process developmentGMP characterization GMP batch developmentGMP clinical production and quality control

Clinical protocol development $500,000Clinical protocol developmentAssemble clinical teamIRB submissionRAC submissionFDA submission

Phase I Human Clinical Trial $500,000Commence clinical protocol

Total estimated expenses $2,100,000

2001 Project Budget:Percentage Amount

Milestone completed in ‘01 NeededVector and analytic development

100% of $300,000 $300,000

Pre-clinical Studies 80% of $500,000 $400,000GMP clinical grade vector process development

25% of $300,000 $75,000

Clinical protocol development

25%of $500,000 $125,000

Phase I Human Clinical Trial

0% of $500,000 $0

Total estimated expenses for 2001

$900,000

2002 Project Budget: Percentage Amount

Milestone completed in ‘02 NeededVector and analytic development

100% of $300,000 $0

Pre-clinical Studies 20% of $500,000 $100,000GMP clinical grade vector process development

75% of $300,000 $225,000

Clinical protocol development

75%of $500,000 $375,000

Phase I Human Clinical Trial

0% of $500,000 $0

Total estimated expenses for 2002

$700,000

2003 Project Budget:Percentage Amount

Milestone completed in ‘03 NeededVector and analytic development

100% of $300,000 $0

Pre-clinical Studies 100% of $500,000 $0GMP clinical grade vector process development

100% of $300,000 $0

Clinical protocol development

100%of $500,000 $0

Phase I Human Clinical Trial

100% of $500,000 $500,000

Total estimated expenses for 2003

$500,000

Budget Explanation

The project costs are associated with the milestones defined in the work plan.These expenses are supported from actual cost of salaries, supplies, laboratory specimens, equipment, and production materials. These cost are in-line with the CLN2 AAV Gene Therapy Business Plan, which was developed in March of 2000. This business plan was reviewed by a number of major biotech companies, such as Genzyme, Avigen, Targeted Genetics, and Cell Genesys. The consensus from these companies was that the expenses would be low for their organizations to perform this work, but an independent Non-For-Profit foundation could accomplish the necessary tasks near the defined costs. A large company has more overhead and bureaucracy to involve in a project of this nature. The business plan was presented at a conference at the NIH in May of 2000 to these major biotech companies (Clinical Trial Initiative Conference Summary is available upon request). The required funding of $2 million is justified from the necessary supplies, resources, personnel, and testing.

See appendix for AAV Gene Therapy Business Plan

Nathan’s Battle Financial InformationFinancial Statement Information

The Nathan’s Battle Foundation was formally incorporated on 3/27/00 and received the formal letter of 501(c)(3) determination in May of 2000. The Foundation does not currently have a formal financial statement prepared from our CPA firm, but one is currently being prepared to comply with the Non-For-Profit filing dates.

In summary given the currently planned fund raising events, the Nathan’s Battle Foundation needs to raise over $652,000 to support the therapy development projects for the 2001 fiscal year. For the fiscal year 2002 given the forecasted event revenue, the foundation needs to raise an additional $605,500 to fund therapy development projects. This funding is necessary to continue the development of therapies for LINCL. Receiving all of the necessary funding in Q3 of 2001 is imperative and for 2002 by Q2. The earlier in the year is important to the viability of the project, without timely funding the project will stop. Total additional funding needed for the next two years of 2001 and 2002, given planned and forecasted events, is $1,257,500. The 2003’s forecasted required funding amount needed for the clinical trial initiation stage of the project is expected to be $500,000. Estimated total funding needed is $1,757,000. The project could be accelerated if we were able to secure the total $1,757,000 up front. Having the funding now would enable us to perform more project tasks in parallel because of the additional resources available to perform the work sooner. The critical path of the project is less than 18 months to the clinic but with restricted funding resources the project will take up to 30 months.. If we can secure the total funding in 2001 the project could be shortened and kids could receive therapy more quickly. The revenues and expenses are as follows:

1999 Revenues and Expenses

1999 Revenue AmountThe Nathan’s Battle Benefit Dinner $91,263.75The Nathan’s Battle Golf outing $16,969Misc. Donations $4,528.51Interest Paid $1,111.19Total Revenue $113,872.49

1999 ExpensesThe Nathan’s Battle Benefit Dinner $2,083The Nathan’s Battle Golf outing $3,475.75NCLRA Research Conference $2,713

Total 1999 Expenses $8,271.75

2000 Revenues and Expenses

2000 Revenue AmountRingling Brothers and Barnum Bailey Circus – Nathan’s Battle Under the Big Top

$95,000

The Nathan’s Battle Golf outing $10,500Jeff and Teri Stoops sale of car donated $16,500Grants and Awards – Ruth Lilly $5,000Misc. Donations $15,000Interest Paid $1,800Total 2000 Revenue $143,800

2000 ExpensesWashington University CLN2 Gene Therapy Research – Dr. Sands’s Lab

$20,000

The Nathan’s Battle Under the Big Top $2,583The Nathan’s Battle Golf outing $2,075.75NCLRA’s Clinical Trial Initiative Conference – May 2000

$3,000

Cornell Feasibility Study $125,000

Total 2000 Expenses $152,658.75

2001 Revenues and Expenses Forecast

2001 Forecasted Revenues AmountThe Natalie Fund for Childhood Brain Disease Research – CA.

$130,000

The Bobbie Shone Trust – England* $20,000The Nathan’s Battle Golf outings* $60,500Grants and Awards* $5,000Misc. Donations $45,000Run Walk Event $22,000Benefit Concert $23,000Dinner Benefit at the Ritz* $50,000Interest Paid $4,500Philanthropic or Future Grant Support* (?)Total 2001 Revenue $360,000 + (?)

2001 Forecasted ExpensesCornell Clinical Trial Project $900,000Dinner Benefit at the Ritz expenses* $3,000The Nathan’s Battle Golf outings* $4,000Misc. event expenses $5,000High Through Put CLN2 Drug Screening* $100,000

Total 2001 Expenses $1,012,000

* These line items are forecasted revenues or expenses that have not actually been received or incurred.

The 2001 amount needed to raise including currently planned forecasted events is $652,000 ($1,012,000 - $360,000 = $652,000).

2002 Revenues and Expenses Forecast

2002 Forecasted Revenues AmountThe Natalie Fund for Childhood Brain Disease Research – CA.

$60,000

The Nathan’s Battle Golf outings $50,000Grants and Awards $5,000Misc. Donations $30,000Interest Paid $4,500Philanthropic or Future Grant Support (?)Total 2002 Revenue $149,500 + (?)

2002 Forecasted ExpensesCornell Clinical Trial Project $700,000Misc. event expenses $5,000High Through Put CLN2 Drug Screening $50,000

Total 2002 Expenses $755,000

The 2002 amount needed to raise including currently planned forecasted events is $605,500 (755,000 - $149,500 = $605,500).

Total additional funding needed for the next two years of 2001 and 2002, given planned and forecasted events, is $1,257,500. The 2003’s forecasted required funding needed for the clinical trial initiation stage of the project is expected to be near $500,000. Estimated total funding needed is $1,700,000.

Balance Sheet Information

1999 Assets and Liabilities

1999 Assets AmountCash $105,540.74Other Assets $0Total Assets $105,540.74

1999 LiabilitiesOutstanding Debt $0

Total 1999 Liabilities $0

2000 Assets and Liabilities

2000 Assets AmountCash $96,681.99Other Assets $0Total Assets $96,681.99

2000 LiabilitiesOutstanding Debt $0

Total 2000 Liabilities $0

Impact of Grant

These children deserve a right to live a full life and have a fighting chance. But, that right will not come without a cure for a disease that takes everything from them. A disease that takes their abilities, their newfound skills and eventually their hope and spirit. They need your help. They need these trials to continue.

Completion of clinical trials will provide scientists and the community with vital information to assist in many rare diseases. The results, in particular, are anticipated to prove as a cure for Late Infantile Batten Disease (CLN2). This successful completion of clinical trials will save the lives of over 500 children directly. In addition, it will improve the quality of life not only for the children who unfortunately have been diagnoses with Batten’s disease. It will also serve as a mechanism for improving the quality of life for all those who are intimately involved with that child.

In addition, the completion of gene transfer therapy is anticipating having positive results for over 40 other rare diseases, which affect hundreds of thousands of people. And, their lives could become more promising and fulfilling through these clinical trails. The results of these clinical trials have far reaching impact. Gene transfer therapy can serve to cure this disease, can improve the chance of cures for other diseases and will improve the quality of scientific information that is available. The information gained from this research and clinical trials will provide key information and knowledge that can be utilized in future research and clinical trials for various other rare diseases.

Rational

Gene transfer therapy clinical trials must be completed to save the lives of these children. If these trials are not perused then these children will die. And, those intimately involved with these children will run the risk of loosing all hope and spirit. These children have no other alternative at this time and time is of a crucial factor. Perhaps other options will come about in the years to come. Unfortunately, these children do not have years to come and everyday must be utilized to its fullest.

Nathan’s Battle Foundation can serve in the best position to institute these clinical trials because they have established several crucial relationships to ensure the trials are completed on a timely and efficiently way. They have already established the needed relationship with Cornell University who will be able to initiate the trials. They have been working in conjointly with The National Ceroid Lipofuscinoses Research Alliance (NCLRA). And, they have coordinated relationship with leading scientists.

As an organization that is true to their mission, Nathan’s Battle Foundation has the reputation and dedication to ensure these trials are completed. Nathan’s Battle Foundation has strived to coordinate efforts with all key stakeholders. In addition, they are open via publications and web site about all issues they are involved in. They communicate effectively what is occurring with the clinical trials, what is needed and why it is needed.

If these clinical trials are not completed the financial costs will result in the healthcare that is needed to sustain these children’s final days. The human costs will be the true price that will be paid. For, the financial impact is minimal. But, for these 500 plus children their lives are o the line and everyday, every minute truly is where the costs are shown. If the clinical trials are delayed many of these children will face the same result, death. Others will begin declining in their abilities. As a delay where to exist, the longer the delay, and the more deaths this disease will cause.

Staff and Facilities

The Institute of Genetic Medicine Weill Medical College of Cornell University will perform the Gene Therapy project for Late Infantile Batten Disease. The Weill Medical College has a state of the art facility that was newly renovated in 1999 to make it a world-class facility. This facility is one of the only laboratories that have the capability of manufacturing clinical grade AAV GMP vector.

The Institute of Genetic Medicine at the Weill Medical College of Cornell University is lead by Dr. Ronald Crystal. Dr. Ronal Crystal is a world renown leader in the gene therapy field. Dr. Crytsal has taken potential therapies to the FDA and has experience executing and performing clinical trials. Dr. Crystal’s leadership of this project ensures the success of this extremely promising project. The excitement in the scientific community regarding this project will foster the necessary collaborations to provide the nations best experts to give guidance and direction.

The project will be managed by a partnership between the Cornell Institute of Genetic Medicine and Nathan’s Battle Foundation. This partnership ensures the success of the trial based on the main focus of each party involved. The Nathan’s Battle Foundation will ensure that the project will be focused and progresses to accomplish milestones on an aggressive schedule. The NBF will utilize its managerial skills and developed relationships to aid in propelling the project to the clinic.

Appendices

AAV Gene Therapy Business PlanCornell Project Feasibility Study Proposal for stages 1 and 2Cornell Feasibility Study cover letterCornell Project Work PlanNon-For-Profit Therapy Development Model DiagramFeasibility Study of Gene Therapy of Late Infantile Neuronal Ceroid Lipofuscinosis (available upon request 56 pages)Clinical Trial Initiative Conference Summary (available upon request 51 pages)