Cooperating for a worthy cause

Eli Lilly, Merck and IDRI tackle global threat of TB

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SEATTLE—When it comes to drug research and development, the focus is usually on targeting drug candidates for high-profile diseases such as myriad forms of cancer that impact people worldwide.

With a finite amount of both finances and research power, the effort to develop drugs targeting diseases that inordinately affect the world's poor populations often is seemingly put on the back burner.

Eli Lilly & Co.
is taking a different approach, opening its labs and amassing a molecular library of more than 500,000 compounds in a search it hopes will develop drug candidates targeting tuberculosis.

Lilly's TB Drug Discovery Initiative was created in mid-2007 and includes the Infectious Disease Research Institute (IDRI), a nonprofit organization, and the NIH's National Institute of Allergy & Infectious Diseases (NIAID).

The competitive nature of drug research was put aside as Lilly worked with Merck & Co. to amass the repository of compounds now being scoured by IDRI scientists.

Dr. Gail Cassell, Lilly's vice president of scientific affairs, says that for pharmaceutical firms, opening the doors to their libraries is "like opening our heart and soul."

"There are beginning be to discussions about precompetitive collaborations in a number of areas in drug research and drug development," Cassell says. "For this to happen in neglected diseases is very unique."

Steve Reed, founder and senior vice president of research for IDRI, says companies eschewing competition for a greater cause may be a new trend.

"Access to libraries has set a new paradigm in the industry," says Reed. "Next to personnel, libraries are a company's second most valuable asset. They don't give them out lightly."

Over the past year, The Lilly TB Drug Discovery Initiative has organized operations and labs and identified compounds for the first round of work. It is performing high-throughput screening of new, validated targets against well-characterized chemical libraries.

According to Cassell, the initiative also will study the potential of a new class of antibiotics from the British biotech firm Summit and CPZEN-45 from Tokyo-based Microbial Chemistry Research Foundation.

Reed said scientists at IDRI are pleased with the promise of CPZEN-45, an early stage clinical candidate which may have a new mechanism of action against TB, and also shows efficacy against multidrug-resistant and extensively drug resistant TB infected mice without any detectable side effect so far examined.

"We think they both have good potential," says Reed. "They may have some resistance to multi-drug resistant organisms. We don't have final information on the mechanism of action. One of the real advantages of having a new compound with activity like this is that it allows you to define the target that it is using to inhibit the organism. Finding that target can expand our ability to identify other drugs."

Lilly has been a driving force behind the research efforts at IDRI, providing more than $9 million worth of gear and $6 million in seed money for five years of research. Lilly acquired much of the equipment when it paid $2.1 billion for Seattle-based Icos in 2006.

Even with such a solid foundation, there still are plenty of hurdles to clear to achieve success.

"You really have to have people with a lot of experience," says Reed. "At IDRI, we are fortunate, as part of the program, to have access to people with experience and the ability to use the high-throughput robotics necessary to go through such a large library."

Cassell notes that conducting screenings on such a large number of compounds is an expensive undertaking, one that likely wouldn't be possible without the high-throughput screenings.

"The IDRI scientists will do the screenings and the follow up screenings to validate any hits that come out of the screen. If you validate the hit, you will then come up with the optimum compound that can be documented as having activity in inhibiting the growth of the TB organism."

The lab established at IDRI includes several high-speed robots, which can analyze hundreds of compounds simultaneously for anti-TB effects. And with the vast amount of information generated as the library is scoured, data management also is crucial, notes Reed.

"The other challenge is to bring into play very good screens," Reed adds. "At IDRI, we can screen biochemical targets as well as the whole organism itself."

While there are a number of tuberculosis drugs available today, some which have been on the market since the 1950s, strains are becoming resistant to these drugs and Cassell points out it is vital to have new drugs in the pipeline, especially since TB is often treated with a combination of drugs, increasing the number of candidates needed.

"Success can be measured by new clinical candidates that can be moved into evaluation," Cassell says. "You have to have multiple shots on goal to be successful even once. We will measure success on clinical candidates that can be evaluated." DDN

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