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Championing Translation

NIH offers essential services to help chemists move promising treatments to clinical trials

by Susan R. Morrissey
November 12, 2007 | A version of this story appeared in Volume 85, Issue 46

Clinic Bound
Credit: Southern Research Institute
Medicinal researchers like the one pictured here from SRI work on translational research, which gets a boost from NIH support.
Credit: Southern Research Institute
Medicinal researchers like the one pictured here from SRI work on translational research, which gets a boost from NIH support.

ACADEMIC RESEARCHERS are becoming increasingly active in drug development, particularly for diseases that are rare or have small commercial markets. To take advantage of this rich area of research, federal agencies such as the National Institutes of Health are providing a variety of resources that make it easier for scientists from fields including chemistry to take their lead compounds deeper into the development pipeline.

In fact, disciplines such as chemistry are crucial to moving promising lead compounds out of the lab and into the clinic—an area known as translational research. Unfortunately, chemistry is an area that has traditionally been underrepresented at NIH, which provides the lion's share of federal resources in this area. To address this shortfall, NIH is doing more to attract chemical researchers and is making available key resources such as grants and contract services to facilitate this work.

The services and advice provided by NIH in many cases come in areas that are unfamiliar to chemists. Having access to such support means that chemists can do what they do best without getting bogged down in developing in vivo animal models to test their small-molecule drug candidates, for example. These services are open to all disciplines and underscore NIH's commitment to translational research.

"NIH, as a leadership agency, must make sure that the translation of its basic science is supported and not abandoned," says NIH Director Elias A. Zerhouni. This support is especially important for those diseases in which the pharmaceutical industry is not interested because treatments for them have little to no commercial market, he adds.

According to Zerhouni, NIH is investing 25% of its research portfolio—spread across its 27 institutes and centers—to support translational work. Although he points out that the NIH portfolio will always remain heavily focused on basic research—60% of its investment is dedicated to this area—he notes that having some funds going to translational research allows the agency "to have a balanced portfolio over a wide range of approaches."

The importance of supporting translational research was underscored when the agency developed the NIH Roadmap for Medical Research more than five years ago. Zerhouni notes that it became clear that the number of scientists who worked in the area of translational research was dwindling. Both basic scientists and clinicians "were telling us that they were seeing an increasing gap in the ability to translate research from basic science to the bedside and a decrease in the number of people who could bridge that gap," he says.

To address this disconnect in the pipeline, 40% of the NIH Roadmap efforts are devoted to translational research. Because the Roadmap is a set of initiatives that cut across the agency's institutes and centers, the resulting opportunities focus on overcoming broad obstacles facing biomedical research.

One of the biggest technical challenges to effective translational research that came to light as the Roadmap was being developed was the lack of capability in chemistry and pharmacology. "I've come to the conclusion that we just don't have enough good chemists in the system," Zerhouni says. "It's not enough to get biological insight by identifying a pathway, a target, and an assay. What you really want to do is intervene, and to do that you need chemistry," he explains.

For interested chemists and other researchers, Zerhouni notes, the Roadmap can help. "We've made focused investments through the Roadmap to provide more tools to translational scientists," he says. These tools include contract services akin to those that are available in industry but too expensive for universities to support.

For example, if a researcher has a small molecule that may be useful in treating a disease such as avian flu or a hepatic fibrosis, he or she can apply to one of NIH's contract programs to have the compound tested for activity in an animal model. Other examples of contract services that are available through the Roadmap and other institute-based programs include synthesis using the Food & Drug Administration's Good Manufacturing Practices rules (GMP) and pharmacokinetic testing.

RESEARCHERS INTERESTED in these services apply and, if selected, will be able to have the necessary work done on their compound by a third party at no cost. NIH sets up the arrangement and pays the contractor directly for the work. The researchers do not directly handle the funds.

Zerhouni says the contract services provide valuable information that not only helps move a compound forward in the development pipeline but also feeds back into NIH research project grants, commonly referred to as RO1s. "It really creates bolder proposals for RO1 grants and allows scientists to go further along the line of translation than they would have otherwise," he says.

The effort to provide such services has led to some criticism that NIH is using federal tax dollars to support research that should be left to the private sector. Zerhouni defends NIH's translational research efforts, noting that it would be irresponsible of NIH to just do fundamental science and not to ensure that promising therapeutics are carried forward. "Pharmaceutical companies just aren't interested in some diseases," he points out.

Found in translation
Credit: Peter Cutts Photography
After receiving input from the community, Zerhouni made translational research a key component of the NIH Roadmap.
Credit: Peter Cutts Photography
After receiving input from the community, Zerhouni made translational research a key component of the NIH Roadmap.

In fact, Christopher P. Austin, director of the NIH Chemical Genomics Center and senior adviser to the director for translational research at NIH's National Human Genome Research Institute, underscores that point, noting that more than 95% of the diseases affecting humans do not have a commercial model or will not support commercial interest. These rare and orphan diseases are just waiting for academic chemists and other researchers to work on them.

According to Austin, the nature of the disease is just one argument for why the Roadmap activities are justified. He also points to the fact that Roadmap initiatives focus on projects in early stages of development and support work on unconventional targets.

"The assay development, high-throughput screening, and chemistry portion of the Roadmap, known as Molecular Libraries, currently develops chemical probes only to the in vitro stage," Austin says. He notes that all of the data that result from Roadmap-funded work are being put in the public domain "because we wanted to provide many starting points to seed downstream research and chemical optimization required for in vivo applications."

THE ROADMAP is also funding work on targets that are outside of those pharma typically works on, such as G-protein-coupled receptors and nuclear hormone receptors, regardless of the potential disease application. More than 90% of the genome is not being pursued as drug targets by pharma, Austin says. "These are areas that will only be worked on by academic researchers."

But Austin acknowledges there is still frequent discussion within NIH as to whether the agency should support true drug development, and if so, how far down the development path NIH should go. "In this era of decreasing budgets, should NIH get into drug development, which is acknowledged by everyone to be difficult and expensive?" he asks.

According to Austin, the answer is yes—in some cases. "If NIH doesn't do this translational work for most rare and orphan diseases, it isn't going to happen at all," he says. "We're producing large numbers of in vitro probes through the Roadmap, putting all of those into the public domain, and hoping a company will pick them up and develop them for therapeutic applications."

For the treatment of rare diseases, however, this model fails, and further translational work is needed to attract biopharma interest. The bulk of that work is in medicinal chemistry. "NIH has not traditionally been a great supporter of chemistry, but that is changing," Austin says.

One Roadmap initiative available to academic chemists and other researchers is the NIH Rapid Access to Interventional Development (NIH-RAID) pilot program. It specifically targets therapeutically interesting small molecules in preclinical development in all therapeutic areas and tries to get them moving down the translation pipeline and into the clinic. The program provides academic and not-for-profit investigators with access to key NIH resources at no cost to the investigator.

"This is not a grant program," says David G. Badman, NIH-RAID program coordinator. Instead, the program is functionally administered through NIH's National Cancer Institute (NCI) Developmental Therapeutics Program to provide services such as large-scale GMP production, formulation, and pharmacokinetic and toxicological testing. The investigator retains intellectual property rights for the compound.

In addition to the contract services provided by the NIH-RAID program, researchers also can get help coming up with an early product development plan. "There is a defined set of tasks that need to be completed and information that needs to go into an Investigational New Drug Application (INDA)," says Raj N. Misra of the Developmental Therapeutics Program at NCI. An INDA must be submitted and allowed by the Food & Drug Administration before clinical trials of a potential drug can begin.

Badman also notes that researchers submitting proposals are encouraged to have an association with a for-profit company interested in stepping in and picking up the compound once it gets further down the pipeline.

"We know that a compound that undergoes initial studies is not necessarily the one that's going to become a drug, but in many of these cases, if the compounds show enough promise, they can be reengineered to improve their efficacy and reduce their toxicity," Badman explains. "So even though a potential drug might not make it all the way through the clinical trial process, we're hoping that enough interest can be generated so that that one or a related compound could be advanced and actually become a drug," he notes.

Stanford University chemistry professor Chaitan Khosla is one of the few chemists who have taken advantage of the NIH-RAID program. He notes that the program helped his group do some critical translational experiments on a project targeting therapeutic agents for neuro-oncological diseases and celiac sprue, an autoimmune intestinal disorder.

"These experiments were focused on one compound," he notes. "The results suggested that we needed to go back to the drawing board to come up with a better compound."

ANOTHER CHEMIST utilizing resources through the NIH-RAID program is F. Ivy Carroll, director of the Center for Organic & Medicinal Chemistry at RTI International, an independent research center in Research Triangle Park, N.C. Carroll tells C&EN that he is using the NIH-RAID program to provide GMP synthesis services for a therapeutic drug that targets cocaine dependence. He adds that he is also taking advantage of preclinical toxicology and pharmacokinetics contract services provided through the National Institute on Drug Abuse (NIDA).

Spinning Ideas
Credit: Southern Research Institute
Yimin Wang conducts a protein purification experiment for drug development in SRI's Structural Biology Program.
Credit: Southern Research Institute
Yimin Wang conducts a protein purification experiment for drug development in SRI's Structural Biology Program.

"The ongoing NIDA and NIH-RAID contract efforts will enable INDA filing and hopefully Phase I clinical studies," Carroll says. "Although we have the capability to conduct many of the required studies at RTI, financial support from NIH is critical during early drug development," he notes.

The NIH-RAID program, although unique in that it's the only program of its type to be NIH-wide, is based on a longtime NCI program of the same name. The NCI-RAID program is just one example of a program offered by some of the larger individual institutes at NIH. These programs target diseases of specific interest for each institute.

The NCI-RAID program has been around in its current form for about 10 years and is open to academicians who have novel small molecules and biologics that target cancer. Like its NIH-RAID counterpart, the NCI version is a contract service program, not a grant program.

Both the NIH-RAID and NCI-RAID programs allow the investigator to retain intellectual property rights to a compound. "Investigators retain full rights and control of their agent and their ability to proceed with future development and partnerships unencumbered once the project is completed," Misra explains. "If they find another partner during the course of the work, appropriate accommodations will be made to transfer the work to the partner with minimal impact on the development."

This flexibility is appreciated by researchers who take advantage of programs like RAID. "We've really benefited tremendously from the government's programs that have helped us push compounds forward," says John A. Secrist III, president and chief executive officer of Southern Research Institute (SRI). "It's been useful because it does allow you to move forward without involving a big pharmaceutical company and its preferences and approaches until late in the game."


Secrist notes that SRI has discovered six cancer-related drugs that moved all the way through the pipeline to get FDA approval with the help of NCI programs. In most cases, he adds, "these drugs were carried forward using only federal funds to a point where they could be licensed to a pharmaceutical company."

Among NCI's other drug development resources is the Drug Development Group (DDG) program for drug candidates that are better identified and of more interest to the institute. These compounds can come from academia, small biotech firms, or large pharmaceutical companies. The program carries these drug candidates through preclinical and clinical stages.

Unlike in the RAID programs, however, clinical studies of compounds in the DDG program are performed under an IND application held by the NCI rather than the investigator. NCI also has greater input in the development and clinical decisions. Intellectual property rights, however, are not usually transferred to NCI.

Another institute that provides drug development resources is the National Institute of Allergy & Infectious Diseases (NIAID), which offers both grants and contract services to academics. The NIAID programs support work on therapeutic drugs in areas such as HIV-AIDS and other infectious diseases.

"Therapeutic grants, particularly in the small-molecule discovery area, do reasonably well in getting funded," explains Carl W. Dieffenbach, acting director of the Division of AIDS at NIAID. The problems come in when investigators try to get funding for drug development.

To address this roadblock in the translational pathway, Dieffenbach says NIAID offers a variety of contract services. The services from his division include both in vitro screening and in vivo animal models to test compounds for activity related to HIV treatment and prevention.

"We have contracts or contractlike activities at every step of the developmental pathway, but they are not strung together," he points out. This is intentional, because the goal is to fill in information as needed so a compound gets to the point where it can be licensed to a for-profit company, he explains.

"Frankly, academic researchers have no business developing a drug," Dieffenbach says. "Academic researchers need to find a way to take their lead compound and get enough data so it can be licensed" to a pharmaceutical company who will carry it through clinical trials.

One area that Dieffenbach says is of growing research interest is whether microbicides can be used as antiviral agents to effectively prevent HIV transmission. He notes that this is an example of an area where academic chemists and other researchers can have an impact.

"There's not a lot of industry interest in this area because it's not a proven concept," Dieffenbach says. He adds that his division can work with academics to have their compounds evaluated in a variety of assays and work them up as potential microbicide leads.

As NIH continues to push to get more chemists into its system, Zerhouni points out that the pace of discoveries of new targets and the need to understand molecular pathways will continue to increase the importance of this key area of science. "The opportunities have never been better for chemistry and pharmacology to really make a difference," he says.

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