Drug Innovation 2000: Orphan Diseases and Global Health Project

Our Mission: Assaying Compounds in Clinical Development for Orphan and Emerging Microbial Diseases

As champions of children diagnosed with rare orphan diseases and other unmet third world medical needs, we recognize an important opportunity within the global drug development community. This opportunity is the challenge to systematically test not only all approved drugs but also those drugs in various stages of clinical development for potential utility in treating orphan childhood diseases and unmet medical needs common to the third world. It is our goal to obtain the set of 2000+ compounds currently in clinical development into a format compatible with high-throughput screening assays and to make this resource available to all non-profit and academic researchers investigating orphan diseases and emerging microbial diseases (e.g., viruses like SARS and bacteria like anthrax) that while most prevalent in the Third World can become global health emergencies.

Rare Diseases Share the Same Molecular Defects with More Prevalent Illnesses

The recent completion of the Human Genome Project has accelerated the identification of the genetic basis for many rare orphan childhood diseases as well as diseases specifically affecting third world populations. For many of these diseases, the newly identified causative gene can be firmly situated within biochemical, signaling or regulatory pathways common to diseases of greater general public health concern such as cancer, heart disease or diabetes. For example, the genes causing each of Neurofibromatosis Type-1, Cowden Disease and Retinoblastoma have all been subsequently shown to be highly relevant to many forms of cancer including breast cancer, glioblastoma multiforme and prostate cancer. Developing a drug useful in treating the symptoms of any one of these diseases may lead to the simultaneous development of drugs with the potential to treat many more commonly occurring cancers.

Targeting a Rare Disease as the First-In-Man Indication
Significantly Reduces Development Time and Costs

Focusing a development program towards an orphan disease can also increase the overall efficiency of executing a specific developmental program. Many orphan diseases are championed by a national community-building non-profit organization (e.g., Tuberous Sclerosis Alliance, Crohn’s and Colitis Foundation of America, Cystic Fibrosis Foundation, Juvenile Diabetes Foundation). These organizations not only serve as a clearinghouse for access to both in vivo and in vitro models of the selected disease but many offer access to a ‘Clinical Alliance’, a coordinated group of medical specialists with strong clinical expertise in the orphan disease who can design clinical trials and then efficiently recruit target patients to execute these in a timely fashion. Most importantly, these organizations serve as the grassroots voice for patients affected with the condition and their families/caregivers. Novartis recognized this opportunity when developing imatinib (Gleevec®), a receptor tyrosine kinase inhibitor expected to be useful against many different types of cancer. Novartis selected Chronic Myelogenous Leukemia, a rare leukemia where over 80% of cases are associated with a specific genetic mutation called the Philadelphia Chromosome, as the first indication for imatinib. Leveraging all of the benefits listed above, imatinib completed all 3 phases of clinical development in 3½ years (compared to the industry standard of 6+). In addition, owing to the strong lobby of patient advocates, the drug was ushered through the FDA approval process in a matter of months and set a new standard for “Best Practices” in drug development.

Old Dogs Can Learn New Tricks: New Indications to Treat Rare Diseases
Are Found For Currently Marketed Drugs

When looking for candidates to treat orphan diseases, the first and easiest place to look would be the set of drugs already on the market. These drugs already have proven safety in the general population and have met Regulatory guidelines with respect to manufacturing, distribution and dispensation. All that is needed is a clinical trial showing the drug’s usefulness to treat the orphan disease. In fact, this approach was recently applied by the research community for Tuberous Sclerosis, a genetic disorder that causes the development of benign growth, or hamartomas, in selected tissues. Rapamycin, also known as sirolimus, has become a standard immunosuppressive drug following kidney transplant. In the past 5 years, scientists have uncovered the mechanism of action for rapamycin, namely that it binds and turns off a protein called mTOR and subsequently shuts down cell growth and protein synthesis so target cells stop working properly. Last year, scientists working on Tuberous Sclerosis have shown that the two causative genes for TSC, tuberin and hamartin also serve to, directly or indirectly, keep mTOR activity in check. Consequently, in patients with Tuberous Sclerosis where either tuberin or hamartin is broken, mTOR activity is increased and cells grow in a somewhat unconstrained fashion with resulting hamartomas. One treatment goal for patients with Tuberous Sclerosis would be to regain control of cell growth and eliminate the hamartomas. Rapamycin, because it can control mTOR, may be a useful solution for Tuberous Sclerosis patients where mTOR is dysregulated. A clinical trial to test this hypothesis will be shortly underway and a successful outcome can, very expeditiously, make this drug available to all patients with Tuberous Sclerosis.

Screening Marketed Compounds is Good; Screening Compounds Under
Development Will Leverage Up-To-Date Industry Know-How

Current reports from the Pharmaceutical Industry state that, on average, 15 years elapse from when a Discovery scientist selects a protein for a drug target until a drug product that modulates the target is approved by the FDA. This suggests that the subset of marketed drugs, including rapamycin and imatinib, represent, on average, the scientific innovation of 15-30 years ago. Most of the current ideas and ‘hot topics’, especially the recent boom in drug target identification and selection owing to the completion of the Human Genome, are not yet represented among the subset of marketed drugs. At best, these drugs are still in late-phase preclinical or clinical development. We believe that the sooner these drugs ‘under development’ are made available to the scientific community championing orphan childhood diseases and diseases common to the third world to test for clinical relevance to these medical conditions, the quicker patients in need can have access to useful and potentially life-saving medicines. Below, we propose a mechanism by which all investigational new drugs in clinical development can be made available to non-profit and academic groups wishing to assay these in validated in vitro or in vivo models of orphan diseases.

A Third-Party Provider Will Collect and Distribute the Developmental Compounds

From an operational standpoint, the feasibility of this goal has already been proven using the set of marketed drugs. Microsource Discovery Systems, Inc. of Gaylordsville, CT, commercially offers The Spectrum Collection™, a high-throughput screening-ready array of 2,000 biologically active compounds including over 1,000 of the currently marketed drugs. The National Institute of Neurological Diseases and Stroke (NINDS) acquired this library for distribution to non-profit and academic groups investigating neurological disorders. Under this program, many scientists have had access to the compound set and useful compounds are being pursued. Results of this screen for Amyotrophic Lateral Sclerosis (ALS) can be found at www.alsa.org/news/news052201.cfm. Following this lead, our own research program at the Rothberg Institute for Childhood Diseases has screened this library in our in vitro cell growth assay for compounds selective in suppressing/killing Tuberous Sclerosis-derived cells while sparing comparable wild-type cells. Of the 2,000 compounds screened, 1 compound met our criteria for a hit and we are avidly performing follow-on experiments to validate its candidacy as a novel drug capable of managing symptoms associated with Tuberous Sclerosis.

Cross-Industry Collaboration To Accelerate Drug Development for Orphan
and Emerging Microbial Indications

Our challenge is put forth to all pharmaceutical and biotechnology companies that have small molecule compounds with active IND applications and whose manufacturing processes are sufficiently robust such that compound availability is not limiting to contribute a sample of each investigational compound to this project. With the help of a 3rd party distributor with a proven track record in this area, we will then coordinate an effort to distribute the library to interested investigators. We will measure success by the number of IND applications submitted from this set of compounds in support of orphan childhood diseases and emerging microbial diseases common to the Third World.

Sincerely,

Bonnie E. Gould Rothberg MD

Bonnie E. Gould Rothberg, MD
Director of Clinical Development
The Rothberg Institute for Childhood Diseases

Jonathan M. Rothberg PhD

Jonathan M. Rothberg, PhD
Chairman
The Rothberg Institute for Childhood Diseases

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