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Teaching An Old Drug New Tricks

Gene Logic is convincing big pharma to take another look at abandoned drugs

by Lisa M. Jarvis
February 13, 2006 | A version of this story appeared in Volume 84, Issue 7

Credit: Gene Logic Photo
Scott Malstrom, head of Gene Logic's in vivo imaging department, uses bioluminescence imaging to determine where a drug is active in a genetically engineered mouse.
Credit: Gene Logic Photo
Scott Malstrom, head of Gene Logic's in vivo imaging department, uses bioluminescence imaging to determine where a drug is active in a genetically engineered mouse.

With the number of new drugs approved dipping in 2005 to its lowest level in more than a decade, the pressure on pharmaceutical companies to bulk up their late-stage pipelines is acute. In-licensing is a popular solution, but the number of late-stage compounds up for grabs is limited, and competition has pushed the cost of licensing deals to exorbitant levels.

Gaithersburg, Md.-based Gene Logic is trying to persuade big pharma to add another approach to its drug development efforts: looking within their own cupboards to find new value in drugs that have been shelved after disappointing trial results. The idea is that compounds that were found to be safe in Phase I trials but not effective in Phase II or beyond could still be useful in other indications.

The underlying concept, known as drug repositioning or repurposing, is not new. Several blockbuster drugs have resurfaced under new guises after setbacks. For example, Pfizer's Viagra and Rogaine both originally failed as antihypertensives, but patients in clinical trials reported side effects that signaled the drug's potential in other indications.

Lilly's cancer drug Gemzar was first developed as an antiviral. And thalidomide, a sleep aid that was never approved in the U.S. because it was found to cause serious birth defects, is now on the market to treat leprosy and could gain approval later this year as a treatment for multiple myeloma, a type of blood cancer.

Gene Logic is encouraging pharma to rely on more than serendipity to revive old products. The company believes its technology platform will enable the drug industry to systematically reexamine compounds-including some that have sat idle for more than a decade-and decide if there might still be life in them.

Credit: Gene Logic Photo
Credit: Gene Logic Photo

"It's a 'reverse biotech' model," says Mark D. Gessler, president and chief executive officer of Gene Logic, which introduced its drug-repositioning program in 2004. "The rest of the biotech industry is out there searching for biology and compounds that can impact that biology. We're starting with a compound that is known to be safe in humans and asking, 'Where could it have an impact?' "

Several other companies are pursuing drug repositioning by in-licensing abandoned compounds for their own pipelines or offering repositioning on a fee-for-service basis to fund internal development. Gene Logic, by contrast, is looking to partner with pharma companies to help jump-start drugs that have stalled in late-stage development. In return, it will share in the rewards if a drug is put back on the market.

"At most pharma companies, once a compound is launched, there's a whole life cycle [management process] in place to explore new uses for that compound," Gessler says. Yet most firms lack a similar mechanism for handling a discontinued drug. "There's no vice president of failed drugs," he says.


Several Models Exist For Reviving Discontinued Drugs

Though Gene Logic is unique in its focus on partnering to help big pharma salvage discontinued drugs, a slew of companies are pursuing other repositioning models. Many are mining the drug development graveyard to fill their own pipelines and fund internal R&D, while others are searching for new uses for drugs that have made it to the market. In both cases, most companies plan to out-license the drugs back to pharmaceutical companies once they have determined a new clinical pathway for the product.

The Japanese drug discovery company Sosei pursues new indications for both marketed drugs and compounds that have been abandoned in development. Sosei either makes chemical modifications to the molecule or comes up with a new drug delivery method, in both cases generating new intellectual property in the process. The company's repositioning program has helped to fill its pipeline, which boasts three products in Phase II, two in Phase I, and a host of compounds in preclinicaldevelopment.

Melior Discovery offers repositioning on a fee-for-service basis but uses the proceeds to acquire and develop compounds for its own pipeline. The company is targeting two areas: in-licensing abandoned or discontinued compounds and pursuing new indications for compounds with expired composition-of-matter patents.

"Our 'sweet spot' is in discontinued clinical Phase II and III compounds," notes Andrew Reaume, Melior's president and chief executive officer.

CombinatoRx takes combinations of known, approved drugs and tries to find new uses, or "patterns of activity," for them. The company has four steroid amplifier products in Phase II trials to test whether combining a reduced-dose corticosteroid with a second compound can enhance anti-inflammatory activity and reduce side effects. The company has in Phase I cancer trials a combination of chlorpromazine and pentamidine, which are marketed as an antipsychotic and a pneumonia treatment, respectively.

Meanwhile, Cypress Bioscience is taking a niche approach, focusing on acquiring or in-licensing central nervous system compounds and repositioning them to treat functional somatic syndromes.


As a result, Gene Logic estimates, roughly 2,000 compounds are sitting idle at big drug companies after failing in Phase II or Phase III trials. It projects that the industry shelves another 150 to 200 drugs at those stages each year. "Our objective is to take compounds that are discontinued, reinterrogate those with the idea of finding new, unanticipated indication space, and create a new clinical path forward," Gessler says.

Not all compounds are ripe for the company's drug-repositioning program. Gene Logic is concentrating on drugs that were discontinued after Phase II but did not demonstrate any significant safety issues. Though the company's technology platform is able to analyze any kind of drug, including biologics, the focus now is on orally available, small-molecule drugs.

Gene Logic entered the drug-repositioning business through its 2004 acquisition of Millennium Pharmaceuticals' repurposing technology program. The deal brought in vivo imaging capabilities, which employ transgenic animals to understand where a compound is active in the body; in vitro cell-based profiling technologies, which monitor how a drug impacts a disease pathway; and ex vivo analysis through a metabolomics program.

Gene Logic started in 1994, focused on offering genomics technology and bioinformatics systems. The centerpiece of its business was a bioinformatics platform comprising an enormous collection of human and animal tissue samples that were analyzed with gene chip arrays from Affymetrix. As the company was assembling that platform, patterns began to emerge, Gessler says. "Every patient is on some form of medication, and we started to see clues about how drugs impact nontarget organs."

As early as 2001, the company saw how its bioinformatics platform could be used as part of a drug-repurposing service, but it lacked the capital to build the other necessary technology pieces from scratch. The Millennium technology, acquired for just $9 million, enabled an immediate launch into the drug-repositioning business.

With a full arsenal of drug discovery technology at its disposal, Gene Logic comes at a compound from every angle, thereby enabling a rapid turnaround. In the first nine months of 2005, Gene Logic says, it initiated work on 20 compounds. A new potential clinical indication or "hypothesis" was identified for each of six compounds. Of these, two are the subjects of advanced discussions to determine whether to take the next step: animal model validation.

Four customers-Millennium, Pfizer, Roche, and an undisclosed company-have enrolled in the program.

For each venture, Gene Logic is taking on all the initial risk in the hopes of substantial reward. The publicly traded biotech of 450 employees is solely responsible for funding the research, but it will receive milestone payments if a partner puts a compound back in the clinic. If a drug finally makes it to market, Gene Logic will enjoy a healthy slice of the sales, either through royalty payments or co-ownership rights.

"This model is unique," says Lee E. Babiss, vice president for preclinical R&D at Roche. "Gene Logic is taking on more risk, but they have more to gain if they are successful." Although Roche is not initially putting up any cash, "we are providing them with very valuable assets," Babiss notes.

Roche is Gene Logic's most recent customer. Roche had already initiated an internal effort to sort through its backlog of discontinued drugs to determine which compounds had been shelved because of toxicity reasons, which had been safe but had not met their primary endpoint during clinical trials, and which compounds should be out-licensed.

The partnership expands on that effort by spanning the entire range of therapeutic categories at Roche including drugs that were dropped from development both recently and many years ago. "Some of these drugs are over 15 years old," Babiss says. "Science has changed a lot since then."

Another attractive feature for Roche is the speed at which Gene Logic can process the drugs. It takes as little as six to 12 months to complete a battery of tests to determine a new clinical pathway for the compounds. Gene Logic then recommends which candidates are most viable, and its partner decides whether to test the model in vivo with animal model validation.

If a compound is given the green light after the animal model validation, the next step is to put the drug directly back into Phase IIa trials, immediately reentering the late-stage pipeline.

This approach is relatively unusual among the companies that boast repositioning or repurposing technology, Babiss says. Other companies that approached Roche "were more focused on applying chemical modifications to existing clinical compounds and then dialing in attributes that address why the compound did not meet the clinical endpoint and/or safety margins," he says.

Looking at the chemistry of the molecule means a program must be restarted with a traditional Phase I study. Furthermore, the research focus is kept on the original indication rather than new ones.

Looking ahead, Gene Logic is aiming to add to its roster of partners and expects to be able to process 30 compounds in 2006. The drug-repositioning program is expected to cost the company roughly $14 million annually, with the hopes of bringing in revenues after 2007.


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