TRND Research Leads to NIH Trial to Test Drug for Niemann-Pick Type C1

Niemann-Pick disease type C1 is a rare, inherited disease characterized by progressive impairment of motor and intellectual functions in early childhood. Life expectancy often does not exceed an individual’s teenage years. To date, the disease is incurable, and no drugs approved by the Food and Drug Administration are available to treat it. In 2009, the NIH Therapeutics for Rare and Neglected Diseases (TRND) program, which is led now by NCATS, chose to repurpose chemical substance called cyclodextrin, normally used as an inactive ingredient in certain formulated drug products, as a potential therapeutic for Niemann-Pick type C1.

Today, a promising new treatment is on the horizon. On Jan. 23, 2013, NIH initiated a Phase I clinical trial to evaluate the safety and effectiveness of cyclodextrin as a potential therapy for Niemann-Pick type C1. This progress is the result of the collaborative efforts of an award-winning, multidisciplinary team of experts from NCATS, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke (NINDS), and the National Human Genome Research Institute; Janssen Research & Development, LLC; Washington University in St. Louis School of Medicine; Albert Einstein School of Medicine, New York City; and University of Pennsylvania, Philadelphia.

A number of family support groups have made significant contributions that have led to the launch of the clinical trial through the funding of Niemann-Pick research and patient support. They include the Ara Parshegian Medical Research Foundation, the International Niemann Pick Disease Alliance, the National Niemann Pick Disease Foundation, and Support of Accelerated Research for Niemann-Pick type C. In addition, the Office of Rare Disease Research, prior to joining NCATS, provided early support for the work through an NIH Bedside-to-Bench award to Forbes Porter, M.D., Ph.D., the trial's senior investigator and NICHD clinical director.

Members of the Niemann-Pick C1 project team.

Members of the collaborative Niemann-Pick type C1 project team. (NCATS Photo/Lisa Goodman)

Why does cyclodextrin look so promising? Excessive amounts of cholesterol accumulate within the cells of the liver, spleen and brain of patients with Niemann-Pick type C1. Animal studies conducted by several academic researchers, including TRND collaborators, Steve Walkley, D.V.M., Ph.D., of the Albert Einstein College of Medicine, and Charles Vite, D.V.M., Ph.D., at the University of Pennsylvania, suggested that cyclodextrin can reduce cholesterol storage in cells and improve neuropathology and liver function. Given this evidence, TRND supported studies to evaluate the drug's safety in animals. The program also enabled the development of a test measuring blood levels of a biomarker that increases as a result of cyclodextrin treatment in the laboratory of Daniel Ory, M.D., at Washington University in St. Louis. The clinical trial researchers will use the test to track the drug's effects in participants.

"Initiation of this clinical trial is the culmination of two decades of basic and clinical research to understand and develop therapies for Niemann-Pick type C1," Porter said. "The efforts of the collaborators who make up the TRND team on this project have greatly accelerated translating cyclodextrin from the laboratory to the clinic."

The trial will test multiple doses of cyclodextrin in nine patients to determine a safe dose that will support an expanded Phase II trial to begin to evaluate the effectiveness of the drug. The trial's researchers are in the early stages of collaborating with the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), which is administered by NINDS, to plan a larger, multicenter Phase II trial of cyclodextrin.

During the initial screen that identified cyclodextrin activity in Niemann-Pick type C1 cells, NCATS researchers from the Division of Preclinical Innovation also identified a second potential lead for further study: delta-tocopherol, a form of vitamin E. Early preclinical work has produced promising results.

According to John McKew, Ph.D., acting director of the NCATS Division of Preclinical Innovation, chief of its Therapeutic Development Branch, and director of TRND, "The multidisciplinary nature of this Niemann-Pick collaboration establishes a generalizable model that can be used in the pursuit of treatment candidates for rare and neglected diseases."


Posted February 2013