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DRIVE through the 'valley of death'

By Quinn Eastman, Illustrations by Noma Bliss

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  stroke take-away

"The traditional model of drug development is no longer sustainable."

When Dennis Liotta* makes such a proclamation, it carries weight. Together with his Emory colleague, Raymond Schinazi,† Liotta discovered some of the most successful anti-HIV drugs as well as founded and advised an array of biotechnology companies.

Along with other experts on drug discovery, Liotta is concerned about a growing gap between academic and clinical research. In fact, the transition from laboratory success to human clinical trials has become so difficult that former NIH Director Elias Zerhouni has dubbed it the "valley of death."

University labs excel in discoveries about basic chemistry and biology: studying cells and enzymes and examining models of human diseases in animals. Conventionally, after these discoveries are made, the task of testing the potential drug in humans falls to industry.

But in the past few years, pharmaceutical firms have begun to shy away from sponsorship of early clinical research. Citing increasing risks and costs—the expiration of patents, cost pressures from health care reform, regulatory stringency, and rising costs of clinical trials—pharma leaders are instead focusing on drug candidates that already have made it past some of the early regulatory hurdles.

Small start-up companies are supposed to fill the void. One such company, Pharmasset, was founded in 1998 by, among others, Schinazi and Liotta to discover and develop antiviral drugs. In 2012, Gilead (Nasdaq: GILD) acquired Pharmasset for $11 billion. However, for every successful start-up, there are a dozen or more failures. Companies founded on brilliant ideas may still have difficulty finding funding, may run out of money after encountering regulatory snags, or fail due to lack of an experienced management team to create value and navigate the abyss between funding and product development.

One result of these barriers is fewer clinical trials. According to the clinical trial industry association CenterWatch, the number of clinical trials listed on clinicaltrials.gov, including U.S. and international studies, declined in 2012 to a four-year low.

These developments frustrate researchers like Liotta and his colleagues, who have recently identified compounds in the laboratory that they think could be effective in fighting viruses such as dengue, West Nile, respiratory syncytial virus, and hepatitis C.

To bring these compounds closer to becoming drugs, he and Emory leaders are exploring a different approach. By combining academic, business, and operational capabilities, Drug Innovation Ventures at Emory, or DRIVE, may be able to withstand the harsh financial climate while following the most successfully traveled route across the valley of death.

An alternative route

Universities across the country have established centers for drug discovery, most of which focus on sorting through vast collections of potential drugs to find a handful that show promising results—or "hits"—in laboratory tests.

DRIVE is different. It will take on a task that academic laboratories have generally been unable to do.

The risky and expensive part of drug development is not in finding the hits but rather in seeing whether the potential drug will have the desired effects in humans. Does the drug stay in the body long enough to do good? Does it get to the right organ? Does it damage the liver or kidneys? What is the maximum tolerated dose? Can it be manufactured on a large scale and cost-effectively?

This part of the process is expensive partly because the FDA requires a cache of safety data before allowing a new drug to be tested in humans. Grants from the NIH, which make up the bulk of university research funding, do not cover costs for these studies.

In the past, Emory—like other academic research institutions—has licensed promising research to start-up companies through its Office of Technology Transfer and hoped for the best. DRIVE will allow Emory to manage the process longer and possibly reap a greater return on investment.

For example, DRIVE will have the independence to do some things that traditional university entities can’t, such as license technology from other universities and combine it with technology from Emory, says CEO George Painter. At the same time, DRIVE will have capabilities that standard commercial firms lack, such as access to Emory’s research infrastructure, which includes the Emory Institute for Drug Development (EIDD). Although the organization will be capable of forming for-profit spin-offs, it is set up as a nonprofit to allow funding access from philanthropic foundations.

"We’re not trying to become a pharmaceutical company," Liotta says. "We want to do this in a way that is compatible with the mission of the university."

DRIVE is following a path similar to that taken by nonprofit groups such as the Michael J. Fox Foundation for Parkinson’s Research, the Cystic Fibrosis Foundation, and the Multiple Myeloma Research Foundation. These charities have ventured into the area of sponsoring drug development because they want to accelerate the process from bench to patient. Rather than strategically injecting money, however, DRIVE will be geared toward developing products.

Starting with dengue

One of the viruses that DRIVE will target is the tropical disease dengue, which is a growing public health problem. Transmitted by mosquitoes, dengue can cause fever, headaches, rash, severe muscle and joint pain, and even death.

Research for a dengue vaccine has been complicated. Last year, a large clinical trial in Thailand that tested the most advanced vaccine candidates against dengue announced disappointing results. The vaccine’s efficacy was only 30%, in part because it failed to protect against one type of dengue virus that was the most prevalent in Thailand at the time of the study.

"People in the field joke that we have been 10 years away from having a vaccine for the last 20 years," says Gonzalo Vazquez-Prokopec, an environmental scientist at Emory who studies how dengue is transmitted from person to person. "It’s definitely a complex landscape for vaccine development."

An additional twist is that if someone gets sick with one strain, recovers, and later becomes infected with another strain, that individual is at higher risk for severe forms of the infection that involve internal bleeding, shock, and potentially death. This complexity is a powerful rationale for developing antiviral drugs against dengue.

Over the past 50 years, the incidence of dengue around the world has increased 30-fold, driven by urbanization and population growth. In 2009 and 2010, dengue fever re-emerged for the first time in decades in the United States with an outbreak in Florida. Liotta calls dengue a "disaster waiting to happen."

Although dengue already is an existing problem in many countries, it is categorized as an emerging disease. This means that government agencies—such as the U.S. Department of Defense and others in South America and Southeast Asia—may be potential partners with DRIVE to develop a drug.

Navigating risks

Painter and Liotta return repeatedly to "de-risking" when describing the premise behind DRIVE. How exactly are they able to minimize risk in the drug development process?

Partly, it may come from a focus on antiviral nucleoside analogues, an area in which they have had past success. Nucleoside analogues are drugs that chemically resemble the building blocks of DNA and RNA (nucleosides). They inhibit the mechanism through which viral enzymes copy genetic material. An antiviral nucleoside analogue interferes with those viral enzymes more than it interferes with human enzymes, and those enzymes are similar enough across viruses so that one antiviral compound may have activity against another.

Because of past successes, "we’ve built up some credibility with potential investors there," Painter says.

Another part of DRIVE’s "de-risking" comes from the breadth and depth of experience of its leadership. Painter, who holds undergraduate and doctoral chemistry degrees from Emory, has led antiviral research at commercial pharmaceutical companies, including GlaxoWellcome, Triangle Pharmaceuticals, and Chimerix. DRIVE’s Chief Scientific Officer, Abel De La Rosa, has led scientific and successful product development efforts at biotechnology companies (Digene, Boston Biomedica, Innogenetics, and Visible Genetics), and he spent almost a decade as senior VP of Business Development and Scientific Affairs at Pharmasset before its acquisition by Gilead. DRIVE’s COO, David Perryman, has founded several biotech companies, including, most recently, Zirus, which is focused on host genetics of infectious diseases.

Even so, Painter acknowledges that decision-making in drug development often involves educated guesswork. He thinks of his job as the "pinball wizard," who plays by intuition and sense of smell.

"Scientists are natural optimists," he says. "They have lots of emotional investment in a project. One of the hardest things to do in the pharmaceutical industry is to kill a project, to know when to say ‘stop.’ It all comes down to good decision making during that time."

In addition, another aspect of "de-risking" will come from government funding—for example, in the form of biodefense or preparations for emerging diseases. Commercial companies tend to lack interest in investing money for fighting diseases without a well-established market, but governments can look ahead.

For example, a decade ago, vaccine manufacturing moved out of the United States because of similar concerns about risks and costs. However, support from the Biomedical Advanced Research and Development Authority then led to construction of a Novartis vaccine manufacturing facility in North Carolina that will allow faster, more responsive flu vaccine production in cultured cells. Painter hopes DRIVE will become the recipient of a similar investment in emerging diseases and biodefense.

The EIDD already has received its first grant from the Defense Threat Reduction Agency, part of the Department of Defense, to develop drugs against equine encephalitis viruses. Spread by mosquitoes and found primarily in Central and South America, these viruses can infect humans and horses and are considered potential biologic weapons. The EIDD also is in the preliminary phases of collaborations on antiviral research with the University of Alabama, Georgia State University, and Saint Louis University. Through DRIVE, potential drug candidates from these projects can be shepherded efficiently through the clinical development path.

"We test-drove this approach before coming to Emory," Painter says, "and we think we can make a valuable contribution." EM




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