From Discovery to Patient Care

A paradigm shift in the way drugs are researched and developed

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James Bennett, M.D., Ph.D., is a physician, researcher and the chair of the Department of Neurology in the Virginia Commonwealth University School of Medicine. He is also an inventor on patents protecting the use of a promising new drug compound.

There has been a paradigm shift in how drugs go from conception and discovery to the marketplace and patient care. Once firmly placed in the realm of pharmaceutical companies, drugs are being discovered more and more by investigators at academic medical research centers, including VCU. Many pharmaceutical companies are cutting back or eliminating their research divisions and concentrating solely on drug development and bringing the drug to market.

A significant amount of translational research is taking place at VCU, from studying more effective ways to treat post-cardiac patients to discovering new drug compounds for the treatment of various complex health issues, such as chronic brain diseases and sickle cell disease.

“It is a brave new world,” said Bennett, who is also the founding director of the VCU Parkinson’s and Movement Disorders Center. “In the 20th century, the pharmaceutical industry researched and developed new medications. Academic medical centers like VCU trained the scientists who moved to pharmaceutical companies to do the translational research. In the 21st century, pharmaceutical companies are just concentrating on development. The research has to come from universities. This is our world now.”

What is translational research?

In academic medical research, the term “translational” has become a new buzzword. The goal of translational research is to improve human health by translating scientific discoveries into practical applications as quickly and efficiently as possible.

Such discoveries typically begin at “the bench” with basic research in which scientists study disease at a molecular or cellular level, then progress to the clinical level, or the patient’s “bedside.”

It is important to note that not all translational research conducted at universities is drug-based. It is also practiced in the natural, biological, behavioral and social sciences and results in new medical devices, health education interventions and other technologies.

“Translational research seeks to look at and answer questions in new, innovative ways. Seeking these answers requires a cross-disciplinary approach and collaboration from investigators throughout the university,” said John Clore, M.D., director of the VCU Center for Clinical and Translational Research. “Today’s medical research involves a wide array of disciplines, including but not limited to the life, physical, computer and social sciences, as well as engineering, economics and business.”

Funded through a $20 million Clinical and Translational Science Award by the National Institutes of Health, VCU is part of a nationwide consortium of academic medical centers.  The Center for Clinical and Translational Research is the home for this award and works with investigators within VCU as well as researchers across the country to advance science and foster partnerships to accelerate laboratory discoveries into treatments for patients.

How drugs are discovered

Bennett is a good example of this shift in drug discovery from pharmaceutical companies to physician scientists at academic medical centers.

In 1996, he identified the compound R(+) pramipexole as a candidate therapy for amyotrophic lateral sclerosis, or ALS. He began running lab experiments and, in 2000, sent an Investigational New Drug (IND) application to the Federal Drug Administration (FDA), which was eventually approved.

Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor, in this case Bennett, probably will want to ship the investigational drug to clinical investigators in many states, he must seek an exemption from that legal requirement. The IND is the means through which the sponsor obtains this exemption from the FDA.

A Physician-sponsored IND is submitted by a physician who initiates and conducts investigations of a new drug. Bennett also patented his discovery and has a financial interest in its success. In 2006, Bennett licensed the drug to a start-up company, Knopp Neurosciences (now Knopp Biosciences).

Licensing provides Knopp the legal right to pursue commercial development and also determines how income from drug development will be distributed as royalty payments.

Knopp began designing and carrying out clinical studies at medical research universities across the country to investigate the safety and tolerability of the drug, which was relabeled “dexpramipexole.” 

“The first part of testing a new drug for a particular condition is safety and tolerability,” said Bennett. “Researchers investigate how patients tolerate the drug. Doses are escalated to see how people do. After this step, researchers design a larger study to examine the drug’s effectiveness on disease.”

Knopp has completed its own Phase 2 study of the drug’s possible effectiveness and recently released the results in the prestigious scientific medical journal, Nature Medicine. Knopp has licensed the drug to another company, Biogen-Idec, which will design and complete the Phase 3 study trial.

“The first Biogen Phase 3 trial sought to recruit 800 subjects. When it closed enrollment at the end of August, 2011, there were 950 persons in the study,” Bennett said. “With this large number of participants, Biogen will be able to determine fairly quickly if the drug alters the course of ALS. If the Phase 2 results are repeated in this larger study, the drug might be approved by the FDA sometime later in 2012.”

Two studies in other chronic brain diseases have begun. Kansas University Medical Center is the study site for the initial investigation of using R(+) pramipexole to treat persons with early Alzheimer’s disease.

A second clinical trial recently started at the Hunter Holmes McGuire Veterans Administration Medical Center (VAMC) in Richmond, Va., to study the drug for use in treating patients with Parkinson’s disease.

“The study at the VAMC is designed to be open to both veterans and non-veterans,” Bennett said. “Because our research shows similar molecular abnormalities in ALS, Alzheimer’s and Parkinson’s, I am hopeful that R(+) pramipexole will also slow development of degeneration in brains of individuals afflicted with these other diseases.”

VCU patents drug for sickle cell disease

More than 13 million individuals worldwide are afflicted with sickle cell disease. A hereditary blood disorder, sickle cell disease occurs when the red blood cells form an abnormal crescent, or sickle, shape that block capillaries and other small blood vessels, leading to anemia, stroke and cumulative damage to tissues and organs.

VCU patented the compound 5-HMF, which has been relabeled as Aes-103, for the treatment of sickle cell disease. This new compound was developed by a team from the VCU Institute for Structural Biology and Drug Discovery that included Martin Safo, Ph.D., associate professor of medicinal chemistry, Richmond Danso-Danquah, Ph.D., assistant professor of medicinal chemistry, and Donald Abraham, Ph.D., the Alfred and Frances P. Burger Emeritus Professor of Medicinal Chemistry and biological chemistry and emeritus director of the institute.

“We have discovered a new, safer and more effective anti-sickling agent, 5-HMF,” said Safo. “This compound has a potent anti-sickling effect, and both in vitro and in vivo studies show that 5-HMF inhibits the formation of sickled cells in the blood while carrying a minimal risk.”

The compound was licensed to AesRx, a start-up company in Newton, Mass., for pre-clinical development and initial clinical trials.

“We have developed an excellent relationship with our licensee, a start-up company with highly experienced management that was able to attract national thought leaders to its board and to develop a creative commercialization strategy,” said Ivelina Metcheva, Ph.D., executive director of VCU Tech Transfer.

Aes-103, currently the only clinical-stage therapeutic that directly targets cell sickling, has received an IND approval from the FDA, and is one of the first molecules to enter the National Institutes of Health Therapeutics for Rare and Neglected Diseases program. The NIH, through a $5+ million grant, is supporting the manufacture, pre-clinical studies and the first three human trials of Aes-103.

“Francis Collins, M.D., Ph.D., the director of the National Institutes of Health, has held this project up as a prime example of translational medicine with academic medical centers working with start-up companies in the research and development of life-changing drug therapies,” said Francis Macrina, Ph.D., VCU vice president for research.

Inventing at a rapid pace

With the assistance and support of VCU Tech Transfer, investigators are discovering new technologies, including drug compounds, which will benefit human health and our quality of life. And they are doing so at an increasingly rapid pace.

Each year, researchers at VCU create more than 100 inventions. Collaborations between researchers within VCU as well as the partnerships between the university and the business community, including venture capitalists, angel investors and start-up companies, have grown impressively and continue to do so.

This acceleration of translational research at VCU underscores the paradigm shift of how drugs and other technologies are discovered and the important role in which universities play within this new world.

At VCU, a strong emphasis has been placed on translational research in its strategic plan, Quest for Distinction, and its vision to be the nation’s top public, urban research university.

“Innovation is a major theme in Quest for Distinction, and our increased emphasis on research and commercialization fits ideally with the highest priorities of any vigorous urban research university,” said VCU President Michael Rao, Ph.D. “A critical component of that research mission is to see that our innovative basic research results get translated into products and services that benefit society.”