Researchers will begin drug development projects for rare and neglected diseases that include potential treatments for a musculoskeletal disorder, a cognitive dysfunction disorder, a virus that affects the central nervous system of newborns, a parasitic worm infection, a form of muscular dystrophy and a rare lung disease. The six new projects are part of the National Institutes of Health's Therapeutics for Rare and Neglected Diseases (TRND) program.
"These projects reinforce NIH's commitment to translational research and the need to accelerate potential new treatments that benefit patients with rare and neglected diseases," said NIH Director Francis S. Collins, M.D., Ph.D. "It is wonderful that TRND scientists and their collaborators can advance such promising projects that may have otherwise remained stalled due to a lack of scientific or fiscal resources."
Congress created the TRND program to facilitate the development of new drugs for rare and neglected diseases. TRND bridges the wide gap in expertise and resources that often exists between basic research discoveries and the development and testing of new drugs in human subjects. As it develops new treatments, TRND also conducts research aimed at improving the drug development process. In contrast to conventional drug development efforts, TRND will publish successes and failures so that the broader drug development community can benefit from the work done.
To develop new medicines, TRND establishes partnerships with academic, government, biopharmaceutical and patient advocacy groups. TRND and its collaborators focus on the optimization and pre-clinical development of new drugs, as needed, advancing them from Food and Drug Administration (FDA) investigational, new-drug approval to first, in-human clinical trials.
Typically, the success rate for such projects is low, with 80 to 90 percent of projects failing in the pre-clinical phase and never making it to clinical trials. This stage of drug development is called the "Valley of Death."
TRND began five pilot projects to establish the proof-of-principle and operating protocols for the program soon after it was established in 2009. Those projects include potential treatments for the neurodegenerative disease Niemann-Pick type C, the neuromuscular disorder hereditary inclusion body myopathy, the blood disorder sickle cell disease, a rare blood cancer known as chronic lymphocytic leukemia, and the parasitic worm diseases schistosomiasis and hookworm. The chronic lymphocytic leukemia and the sickle cell disease projects have recently received investigational new drug approval from the FDA and are in clinical trials.
Earlier this year, TRND approved its first four drug development projects from its initial solicitation. They focus on potential new treatments for Duchenne muscular dystrophy, a degenerative muscle disorder; fragile X syndrome, the most common inherited form of cognitive and developmental disabilities; cryptococcal meningitis, an infectious fungal disease; and core binding factor leukemia, a rare blood and bone marrow cancer.
"TRND selects projects based on their potential to move forward into human trials and transform patient care in diseases for which there is little or no therapy," said Christopher P. Austin, M.D., scientific director of the NIH Center for Translational Therapeutics, which oversees TRND and is administered by the National Human Genome Research Institute (NHGRI). "While such projects are high-risk, the scientific opportunities and medical needs are compelling. After rigorous scientific review, the new projects were selected to maximize the chance of success and to teach us important generalizable lessons about rare and neglected disease drug development."
The latest TRND projects, approved by the advisory council of the National Institute of Neurological Disorders and Stroke (NINDS) on behalf of NIH, and the collaborating principal investigators are:
An inhibitor compound for treatment of fibrodysplasia ossificans progressiva.
Kenneth D. Bloch, M.D., William T. G. Morton Professor of Anesthesia
Harvard Medical School, Massachusetts General Hospital, Boston.
Fibrodysplasia ossificans progressiva is a rare inherited disorder where muscle and connective tissue such as tendons and ligaments are gradually replaced by bone. The compound under development has shown efficacy in a mouse disease model.
Novel therapy for treatment of creatine transporter deficiency.
Rick Hawkins, Chief Executive Officer
Lumos Pharma, Inc., Austin, Texas.
Creatine transporter deficiency occurs from a mutation in a creatine transporter gene that prevents the transport of sufficient levels of creatine to the brain and results in cognitive function disorder. The lead compound has been evaluated in mice with creatine transporter deficiency and resulted in improved brain metabolism and cognitive function.
A compound for treatment of neonatal herpes simplex virus.
David W. Kimberlin, M.D., Professor of Pediatrics
The University of Alabama at Birmingham.
Neonatal herpes simplex virus is an infection transmitted from mother to child during childbirth. In preliminary studies, the candidate compound that will be advanced by this group shows anti-herpetic activity and can penetrate the central nervous system. This compound has received longstanding development support by National Institute of Allergy and Infectious Diseases, including funding of the current clinical trial that will collaborate closely with TRND.
Development of a deuterium-modified compound for treatment of Schistosomiasis.
Julie F. Liu, Ph.D., Director, Research Management
CoNCERT Pharmaceuticals Inc., Lexington, Mass.
Schistosomiasis is a neglected tropical disease caused by parasitic Schistosoma worms that afflicts more than 200 million people worldwide. The disease can cause severe anemia, diarrhea, internal bleeding and/or organ damage. Neglected diseases are conditions that inflict severe health burdens on the world's poorest people. This project aims to produce compounds that retain the positive anti-parasitic effects of the current treatment, praziquantel, which stuns and kills the worms while enabling lower and less frequent doses with potential for improved tolerability. This may allow broader access of a therapeutic to affected patients.
A drug candidate for treatment of Duchenne muscular dystrophy.
Peter Sazani, Ph.D., Executive Director of Preclinical Development
AVI BioPharma, Bothell, Wash.
Duchenne muscular dystrophy is an inherited, rapidly progressive form of muscular dystrophy affecting approximately 1 in 3,500 male births worldwide. This collaboration aims to develop a compound that would treat a sub-group of patients with a specific mutation responsible for Duchenne muscular dystrophy. The team will also investigate the general utility of this innovative treatment platform technology.
A pharmacological therapy for treatment of autoimmune pulmonary alveolar proteinosis.
Bruce C. Trapnell, M.D., Francis R. Luther Professor of Medicine and Pediatrics
Cincinnati Children's Hospital Medical Center-Research Foundation, Cincinnati, Ohio.
Pulmonary alveolar proteinosis is a rare lung disease characterized by the build-up of a grainy material in the air sacs of the lungs that causes breathing difficulties and can result in respiratory failure in rare cases. The protein therapeutic that is the subject of this collaboration will be developed as an inhaled therapy.
TRND has established data-driven milestones for each project to track progress and allow projects which do not achieve milestones in the established timeframe to be terminated, thus allowing other promising candidates to enter the program. A project would be terminated, for example, if the new treatment fails to show effectiveness in animal models, demonstrates toxicity in preclinical testing, or is found not to have the needed bioavailability, the amount of drug absorbed by the body.
"The goal of TRND is to work closely with project partners to achieve scientific milestones that we hope will produce badly needed treatments for underserved patient populations." said NHGRI's John McKew Ph.D., chief of NCTT's Therapeutic Development Branch and director of TRND.
Under TRND's collaborative operational model, project partners do not receive grants. Instead, the partners form joint project teams with TRND and receive in-kind support from TRND drug development scientists, laboratory and contract resources.
The potential treatments are developed and modified as needed to take them through the many steps of the preclinical development process. For projects which fail to progress beyond a milestone and are terminated, efforts will be made to understand the reasons for failure, to improve our understanding of the drug development process and thus improve its efficiency. TRND projects are taken only to the point in development at which they can attract outside funding; beyond this point the partner takes the project through the remainder of clinical development and regulatory approval process.
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