Study Demonstrates Success of NCATS’ Rare Diseases Therapeutic Development Programs

Developing new drugs can take years and cost billions of dollars. Because of the time, expense and likelihood that a promising drug will never make it to market, few companies are willing to investigate new drugs to treat diseases that may not be well understood or provide the potential for a good return on investment.

The picture can be even more challenging when it comes to developing drugs for rare or neglected diseases, because there are a limited number of patients to study and because a relatively small market exists for rare disease drugs. To counter these systematic challenges in the drug development pipeline, NCATS runs two innovative late-stage preclinical drug development programs, Therapeutics for Rare and Neglected Diseases (TRND) and Bridging Interventional Development Gaps (BrIDGs). TRND and BrIDGs collaborations and resources are helping scientists translate basic research discoveries into treatments for patients more efficiently by providing a new collaborative model of early drug development that “de-risks” projects to make new drugs commercially viable and attractive to outside partners.

“There are many roadblocks in the drug development pipeline that prevent promising therapies from making it to people who need them,” said Anton Simeonov, Ph.D., NCATS acting scientific director. “TRND and BrIDGs create solutions to overcome these roadblocks, and not only apply them to particular drug development projects, but also to rigorously assess their effectiveness and disseminate the approaches so that others can use them.”

Have TRND and BrIDGs Worked?

Andrew Lo, Ph.D., Charles E. and Susan T. Harris Professor of Finance, Massachusetts Institute of Technology (MIT) Sloan School of Management, and Nora Yang, Ph.D., director of portfolio management and strategic operations, NCATS Division of Preclinical Innovation, led a collaborative research team that conducted a financial analysis of 28 TRND and BrIDGs projects related to rare diseases. The study, published Feb. 25, 2015, in Science Translational Medicine, found that the scientific and operational processes utilized in TRND and BrIDGs projects led to reduced cost of developing new drugs, reduced financial risks, and effectively provided a way to develop promising therapeutics to the point where they could be handed off to the private sector for final testing and marketing.

“We started the NCATS rare disease therapeutic development program five years ago,” Yang said. “We saw early signs of programmatic success, but we needed an objective measure to quantify its effectiveness. As scientific innovators, we were delighted to be able to work with Professor Lo and his team, who are leaders in financial innovation. We were excited to find that our portfolio yielded even better results than we expected when our TRND-BrIDGs productivity data were analyzed with Professor Lo’s model.”

Although the TRND program is only five years old, one-third of the 28 projects included in this analysis already have attracted independent private funding. Seven compounds from the portfolio have been in clinical testing, including one in a Phase II trial for sickle cell disease. The other compounds in clinical testing are for retinitis pigmentosa, Niemann-Pick disease type C1, GNE myopathy (also known as hereditary inclusion body myopathy), chronic lymphocytic leukemia, beta thalassemia and Friedreich’s ataxia. Two more Investigational New Drug (IND) applications have been successfully filed with the U.S. Food and Drug Administration (FDA), and clinical trials are underway for Duchenne muscular dystrophy and retinitis pigmentosa.

In another mark of success, two larger biopharmaceutical companies acquired two companies that had collaborated with NCATS. The acquiring companies, Baxter and Shire, experienced one-day stock market gains of $238 million and $423 million, respectively, on the days the sales were announced. Two new startup companies were spun out from two of the portfolio projects to continue commercialization of projects de-risked by NCATS.

The NCATS Model

TRND and BrIDGs projects’ lower cost and greater success rates were accompanied by longer preclinical development times than the industry average.

“This result was not unexpected, because the programs take a methodical, step-by-step ‘sequential approach’ that reduces drug development costs,” Yang said.

The sequential approach differs from the industry standard, which undertakes multiple investigations into a new drug simultaneously. This method moves a successful therapeutic more quickly through the pipeline to market, but it can also cost more if a drug fails, because there is more up-front investment.

For each project, NCATS and outside investigators form a project team that develops a project timeline and milestones and defines deliverables and go/no-go milestone criteria. If projects meet all of their milestones, there is greater potential for the therapeutic agent to succeed and that private financing can be secured from pharmaceutical companies, biotechnology companies or venture capitalists. When a project does not meet its milestones, it may be closed out.

The TRND and BrIDGs model provides a way to help drug developers navigate through the so-called “valley of death,” the time after a therapeutic agent emerges from preclinical research but before it has undergone final testing for use with patients.

“We don’t take a product to market, but we can’t ignore marketability,” Yang said. “Whatever project we put public money into, we have to make sure that we build a compelling value proposition so that private investors will carry it forward and get the final medicine to patients.”

The study by the MIT-NCATS team concluded that TRND and BrIDGs provide a realistic business model under which a portfolio of rare-disease therapeutics can yield attractive financial returns. Successful demonstration like this can lead to more private-sector funding for rare-disease therapeutic development, generating system-wide impact on translational sciences. The analysis also suggests that this innovation in translational science and operational models can get more treatments to more people more efficiently and that NCATS can successfully catalyze the partnerships needed to advance translational science.

“It’s been a pleasure to work with NCATS, and our findings suggest tremendously exciting opportunities to do well by doing good through closer collaboration between the financial industry and the biomedical community,” Lo said.

Planning Next Steps

TRND and BrIDGs team members, many of whom worked in the pharmaceutical industry before coming to NCATS, will continue efforts to improve these program models as the next group of projects gets underway.

“This kind of analysis is critical to helping us determine if we truly are meeting our mission of ‘advancing translational sciences,’” Yang said. “Now that we know our programs have produced better success rates and lower costs, we need to understand the factors in our science and operations that underlie the improvement. Understanding these success factors will be crucial for NCATS, through its preclinical therapeutic development programs, to further increase efficiency, and to articulate our models in sufficient detail that others can adopt them.”

“This remarkable collaboration exemplifies a number of NCATS core principles,” said Christopher P. Austin, M.D., NCATS director. “Bringing distinct expertise together — in this case drug development and financial engineering — leads to the greatest advances in science.”

More on TRND and BrIDGs

TRND and BrIDGs researchers provide in-kind resources and expertise to help collaborators complete the necessary investigation and development studies that the FDA requires. Collaborators include academic institutions, biotechnology companies, NIH intramural laboratories, patient groups and pharmaceutical companies.

The drugs currently being developed for rare diseases cover a variety of conditions, including for central nervous system diseases, musculoskeletal diseases, endocrine disorders, cancers and cardiovascular disorders, among others. Five of the current projects involve new uses for existing drugs, 13 for new molecular entities, 8 for large molecules, 1 for stem cell therapy and 1 for gene vector therapy.


Posted February 2015