Over the past few weeks, the National Institutes of Health (NIH) has announced a number of initiatives and programs.  For example, NIH recently announced the Food and Drug Administration’s (FDA) approval of a new oral medication for the treatment of rheumatoid arthritis that represents a new class of drugs for the disease.   

The drug, tofacitinib (Xeljanz), provides a new treatment option for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate, a standard therapy for the disease.  The approval represents a significant government-industry accomplishment and breakthrough.  

Affecting nearly 1.5 million adults, rheumatoid arthritis is an inflammatory disease that causes pain, swelling, stiffness, and loss of function in the joints. It occurs when the immune system, which normally defends the body from outside invaders such as bacteria and viruses, attacks the membrane that lines the joints.  

Tofacitinib is from a new class of drugs developed to target Janus kinases.  One member of this family, JAK3, was discovered in the early 1990s by a National Institutes of Health laboratory in the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).  Subsequent studies carried out at the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the NIAMS, showed that genetic defects in JAK3 can cause severe combined immunodeficiency.  This discovery led to the idea that drugs blocking Janus kinases would suppress the immune system and might be protective against the damaging inflammation of rheumatoid arthritis and certain other autoimmune diseases.  

The approval of tofacitinib represents the first time in a decade that the FDA has approved an oral disease modifying antirheumatic drug, or DMARD, for the treatment of rheumatoid arthritis. This broad class of drugs slows or halts the progression of damage from the disease, rather than merely providing relief from symptoms. Unlike biologic treatments for rheumatoid arthritis — which are also DMARDs and target immune system proteins — tofacitinib is a pill, not an infusion or an injection. It is the first Janus kinase inhibitor to receive an FDA approval for rheumatoid arthritis 

John J. O’Shea, M.D., scientific director of the NIAMS, is the NIH researcher who discovered JAK3 and first cloned the human form of the protein.  In 1993, shortly after O’Shea and his team discovered the JAK3 protein and established its role in inflammation, O’Shea learned that scientists at Pfizer were searching for drug targets to tackle autoimmunity and transplant rejection.  Subsequent discussions led to an innovative public-private collaboration between NIH and Pfizer, through a cooperative research and development agreement.  This agreement allowed teams from both organizations to work together toward the common goal of finding a new immune-suppressing drug for this debilitating disease.  

Warren J. Leonard, M.D., director of the Immunology Center in NHLBI, is a pioneer in immune research whose group first identified the genetic mutations that are responsible for X-linked severe combined immunodeficiency (XSCID), commonly known as the “Bubble Boy Disease.”  Leonard, in collaboration with O’Shea, then demonstrated that the protein that is defective in XSCID associates with JAK3, and that humans with mutations in JAK3 have a form of immunodeficiency clinically similar to XSCID.  That discovery led to their hypothesis that JAK3 inhibitors might be potent immunosuppressive agents, as is the case for tofacitinib. 

NIH BrIDGs program helps overcome research roadblocks 

Finally, NIH recently announced a new program called Bridging Interventional Development Gaps (BrIDGs), which is designed to enable NIH contractors to provide pre-clinical services — such as toxicology studies — for therapeutic projects that have demonstrated efficacy in a disease model.  In other words, the program provides eligible scientists with no-cost access to National Institutes of Health therapeutic development contractor resources. 

Targets for this program include potential new treatments for a variety of cancers, spinal cord injury, and a rare disease that can lead to kidney failure.  The program is called BrIDGs “because there is a lack of private resources or [researchers] hit a roadblock and need additional expertise.  

BrIDGs, formerly known as NIH Rapid Access to Interventional Development, is supported by the NIH Common Fund. I n addition, NIH Institutes and Centers at times contribute funding to support projects relevant to their missions.  The eight-year-old program is led by the NIH’s National Center for Advancing Translational Sciences (NCATS), which we wrote about back in May. 

For the majority of projects, the goal is to enable the submission of an Investigational New Drug (IND) application to FDA.  Human clinical trials using an investigational new drug may commence within 30 days of the submission of an IND for that drug unless the FDA informs the sponsor that the IND is subject to a clinical hold.   

To date, BrIDGs has generated data to support 12 INDs submitted to the FDA, and one clinical trial application to Health Canada. Twelve of the 13 projects have been evaluated in clinical trials.  Three BrIDGs-supported therapeutic agents have gone as far as Phase II human clinical trials, in which researchers give an experimental therapy to a group of patients to evaluate the effectiveness and safety of a treatment.  Third-party investors have licensed six agents during or after their development by BrIDGs. 

“I am excited by the high success rate of this program,” said Christopher P. Austin, M.D., director of NCATS.  “As its name implies, the program bridges the gap between a basic discovery and clinical testing by providing the expertise needed to perform crucial pre-clinical studies, often breathing new life into projects that otherwise may never reach patients.”  BrIDGs selected the following new projects from its 2012 application solicitation: 

Peritoneal Cancers: Tumor Penetrating Microparticles for Peritoneal Cancers, Jessie Au, Pharm.D., Ph.D., chief scientific officer and acting chief executive officer Optimum Therapeutics, LLC, San Diego.  This project focuses on cancers that affect organs in the peritoneal cavity such as the bladder, liver and pancreas.  A drug delivery system, called tumor-penetrating microparticles, is under development to target peritoneal tumors. 

Lecithin-cholesterol acyltransferase (LCAT) deficiency syndrome: Development of Assays to Detect Anti-drug Antibodies against ACP-501 (recombinant human LCAT)
Brian Krause, Ph.D., chief scientific officer, Alphacore Pharma, LLC, Ann Arbor, Mich.
Lecithin-cholesterol acyltransferase deficiency syndrome is a rare disorder that causes a drastic reduction of high-density lipoprotein (HDL) cholesterol levels in patients.  This leads to disorders of the cornea (the transparent lens on the eye), anemia, and may cause kidney failure.  The objective of this project is to develop a treatment called recombinant human LCAT that would act as a replacement therapy to offset the deficiency caused by LCAT deficiency syndrome.  

Spinal Cord Injury: Development of Nogo Receptor Decoy for the Treatment of Spinal Cord Injury, George Maynard, Ph.D., vice president, Preclinical Development Axerion Therapeutics, Inc., New Haven, Conn.  Recovery after a spinal cord injury is limited, as nerve cell growth is virtually nonexistent in the adult spinal cord.  This project aims to develop a compound called Nogo Receptor Decoy to rewire nerve cells that promote the recovery of neurological function.  The NIH’s National Institute of Neurological Disorders and Stroke is co-funding the pre-clinical studies for this project.  

“The success of BrIDGs demonstrates there is a vital need in the research community for the services offered through the program and speaks to the quality of the projects it supports,” said John McKew, Ph.D., chief of the NCATS Therapeutics Development Branch.  “While not all projects will make it as treatments, the support gained through BrIDGs provides each with a shot at success.”” 

BrIDGs solicits applications once a year. The next opportunity to submit applications is from Dec. 1, 2012 to Feb. 1, 2013. The BrIDGs application process will move to the proposalCENTRAL application system, which is a streamlined application process used by some of NIH’s programs.  

New Generation of Scientists  

Finally, NIH recently announced that it is seeking to launch multiple initiatives designed to help strengthen the biomedical research enterprise and sustain the global competitiveness of the U.S. scientific community well into the future.   

Faced with significant challenges affecting the biomedical research workforce and the storage and use of large biomedical datasets, the NIH Director charged the Advisory Committee to the Director (ACD) to develop recommendations.  The ACD used three specialized committee working groups, each of which included additional outside experts on the relevant topics.  

The National Institutes of Health is “The future of biomedical research depends upon our ability to support a research ecosystem that leverages the flood of biomedical data, strengthens the research workforce through diversity, and attracts the next generation of researchers,” said NIH Director Francis S. Collins M.D., Ph.D. “I’m grateful to the experts, both inside NIH and from the broader biomedical research community, who have given these matters extensive thought and made it possible for NIH to put forward actions designed to benefit our entire research community for years to come.” 

The ACD presented its recommendations to the NIH director in June 2012.  NIH leadership further deliberated on the recommendations and presented its implementation plan at the 105th meeting of the ACD on Dec. 6 and 7.  The actions that NIH is seeking to implement are: 

Diversity in the Biomedical Research Workforce:  

• Launch a new NIH program called Building Infrastructure Leading to Diversity (BUILD) intended to provide rigorous mentored research experiences for undergraduate students at participating schools; financial support to pursue biomedical research careers; faculty support for training highly effective mentors; and innovation space to develop new approaches for increasing diversity in the Ph.D. training pathway.
• Establish a National Research Mentoring Network to connect students, postdoctoral fellows, and faculty with experienced mentors; develop standards of good mentorship in biomedical research; and provide workshops and training opportunities in grantsmanship, among other goals.
• Promote fairness in peer review through interventions including implicit bias and diversity awareness training for both scientific review officers and members of review panels, and piloting a program that would make grant applications completely anonymous.
• Increase engagement of NIH leadership by:
  • recruiting a chief diversity officer to coordinate NIH initiatives designed to enhance the diversity of the NIH-funded workforce
  • establishing an NIH steering committee working group on diversity to help ensure that diversity remains a core consideration of NIH governance 

The Future Biomedical Research Workforce:  

• Enhance training of graduate students and postdoctoral researchers:
  • through a grants program that would support innovative approaches to complement traditional research training
  • by encouraging adoption of individual development plans for all trainees

• Explore increased support for training mechanisms designed to accelerate the development of independent research careers, including NIH Pathway to Independence Awards (K99/R00) and Early Independence Awards.
• Increase emphasis on ongoing assessment of the biomedical research workforce, including a proposed follow-up study on clinician scientists.
• Identify and track more comprehensively all graduate students and postdoctoral researchers supported by NIH to provide a sound basis for assessing workforce needs and planning future training activities. More comprehensive career outcomes data also would help to inform prospective graduate students and postdoctoral researchers contemplating careers in biomedical research.  

Data and Informatics:  

• Maximize the value of biomedical data through a new Big Data to Knowledge (BD2K) initiative that would create:
  • improved data and software sharing policies, catalogs of research data, and data/metadata standards development to facilitate broader use of biomedical big data
  • analysis methods and software development and dissemination
  • enhanced training for biomedical big data
  • proposed new centers of excellence

Launch the NIH InfrastructurePlus adaptive environment to advance high-performance computing, agile hosting and storage approaches, and modernization of the network, among other approaches.