NCATS Researchers Propose Innovative Approach to Test Drugs in Rare Diseases

Developing effective treatments is a slow and costly process, and more than 80 percent of investigational drugs tested in clinical trials fail. Discovering treatments for rare diseases can be even more challenging because the small numbers of patients with these diseases make it difficult to find enough people who can participate in clinical trials. The small numbers of rare disease patients also make gathering information about the diseases difficult. As a result, scientists often know little about the symptoms and biology of these conditions, which adds to the complexity of designing drug studies. Additionally, pharmaceutical companies may find it difficult to justify the cost of developing drugs for such small markets of rare disease patients.

There are about 7,000 diseases that affect humans, and treatments are available for fewer than 1,000. That's about 6,000 untreatable diseases. At the current rate of transition from untreatable to treatable, which amounts to a handful of drugs approved each year, it will take more than 1,000 years for every disease we know of now to be treatable.

"NCATS' mission is to get more treatments to more people more quickly," said NCATS Director Christopher P. Austin, M.D. "One way NCATS does this is to approach the universe of diseases in a holistic way, focusing on finding connections among conditions that at first glance may seem unrelated."

In a paper published in the June 6, 2014, issue of Nature Biotechnology, NCATS scientists present an approach to combat the odds in just this way: Pursue treatments by targeting common molecular mechanisms across multiple rare diseases. "It's a proposal for a new way to test drugs and develop better treatments for rare disease patients," said P.J. Brooks, Ph.D., a program director in NCATS' Office of Rare Diseases Research (ORDR) and lead author of the paper.

Currently, scientists design clinical trials by testing one drug in a group of patients with a single disease. In other words, potential treatments currently are tested in only one disease at a time. Instead, the authors say, a more efficient method would be to group patients whose rare diseases are caused by the same type of genetic abnormality and then treat them all with a drug that is designed to address that problem.

For example, several rare diseases are caused by a type of genetic change called a nonsense mutation, which prevents the body from making full-length proteins. Another type of mutation, a missense mutation, can cause abnormal protein folding and also underlies multiple rare diseases. Either type of mutation can result in cystic fibrosis, a life-threatening lung disease; Gaucher disease, which affects the blood-forming organs, bones and nervous system; or Tay-Sachs disease, a neurodegenerative disorder.

Although these diseases differ in their characteristics and affected genes, many people with the conditions have one of the two types of mutations. Therefore, drugs that correct missense or nonsense mutations could be tested in all three diseases. Using this approach, each candidate drug for a specific type of mutation could be tested in a single clinical trial for all three diseases. In the standard clinical trial approach, each drug would be tested separately in each disease, tripling the number of trials needed.

"Research based on shared molecular mechanisms would enable scientists to classify thousands of diseases into a smaller number of categories," Austin said. "This method could reduce the time and costs associated with clinical trials, enhancing the efficiency and pace of getting drugs to rare disease patients."

Targeting missense and nonsense mutations are just two examples. Using DNA sequencing and other genomic technologies — combined with basic research findings to identify disease-related mutations — will continue to help scientists identify many other types of common molecular mechanisms underlying traditionally distinct diseases.

Already, researchers are demonstrating the feasibility of this new approach. A group of scientists across 26 U.S. hospitals, as part of the Children’s Oncology Group supported by the National Cancer Institute, is conducting a treatment study of four pediatric cancers. Each cancer affects different parts of the body, including the blood, lungs and brain. However, mutations that lead to too much activity of the ALK gene underlie each of the four cancers in some patients. The scientists are testing the effectiveness of a drug targeting the ALK gene product to treat all four diseases.

Carrying out this approach in clinical trials of rare diseases ideally would happen through a collaborative network of institutions where multiple scientists are studying different rare diseases, Brooks explained.

This way, researchers could cooperate, share data and ensure high quality of studies more easily. The Rare Diseases Clinical Research Network, coordinated by ORDR, already is taking this approach.

Brooks hopes that the proposal begins a discussion among rare disease researchers, patient groups and industry about better ways to develop treatments for patients with rare diseases.


Posted June 2014