Chronic fatigue syndrome (CFS) has been at the center of a vortex of controversy since the FDA handed down a complete response letter on the Toll-like receptor 3 modulator Ampligen (rintatolimod) from Hemispherx Bioscience Inc. – the only drug in development for CFS – despite the impassioned pleas of patients at an Arthritis Advisory Committee meeting in December 2012. (See BioWorld Today, Dec. 21, 2012, and Feb. 6, 2013.)

Although pressure from those patients and from the Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) Association of America helped to convince the FDA to organize a public workshop in April to discuss strategies to improve regulatory guidance for the disorder, individuals with CFS may benefit from a separate effort to find new indications for drugs that failed to demonstrate efficacy in their initial targets. (See BioWorld Today, March 14, 2013, and May 22, 2013.)

CFIDS collaborated with Biovista Inc., using its clinical outcomes search space, or COSS, technology, to identify two candidates for CFS treatment that are being readied for proof-of-concept trials. The candidates moved to an FDA pre-investigational new drug (IND) meeting, scheduled for the third quarter, less than a year from the project's start, according to Aris Persidis, Biovista's president.

In contrast, the typical timeline to advance a compound through drug discovery and preclinical studies prior to IND filing is three to five years, according to data from the Pharmaceutical Research and Manufacturers of America. And that schedule doesn't count basic research and screening.

"To be able to have enough of an argument that the FDA will grant you a pre-IND within a 12-month period is very, very exciting," Persidis told BioWorld Today.

"There is a big gap in the pipeline that moves basic laboratory research into safe and effective treatments," observed Kimberly McCleary, president and CEO of CFIDS. "Without a bridge to bring discoveries to the clinic, laboratory research rarely becomes more than a paper."

"We understand the CFS knowledge base and know how to fill this gap," added Suzanne Vernon, scientific director of CFIDS. "Biovista recognized the opportunity for discovery."

COSS generates hypotheses about possible clinical outcomes and acquires data from multiple sources, including experiments, interaction and expression databases, reported outcomes, patents and scientific literature.

The tool then goes far beyond data mining, developing unique and standardized data profiles "for every drug, every disease, every adverse event and every molecular target known to modern medicine," Persidis said.

The profiles are compared and ranked to identify the best matches for a given target in a variety of uses, such as finding new drugs for a certain disease or patient subpopulation, suggesting effective drug combinations for a particular condition or discovering comorbidities among patient populations that could increase the risk of adverse events.

COSS "allows us to answer the most important question in translational medicine," Persidis said, "which is 'How can I make sense of the data I have and translate it into something that will affect the patient at the point of care?'"

'Making a Better Bet'

CFS isn't the only indication where COSS is showing mettle. Charlottesville, Va.-based Biovista has collaborations with Pfizer Inc., of New York, and Novartis AG, of Basel, Switzerland, as well as the FDA's Office of Clinical Pharmacology. (See BioWorld Today, Nov. 10, 2010, and BioWorld Insight, Nov. 29, 2010.)

In March, Cambridge, Mass.-based DART Therapeutics Inc. inked an agreement with Biovista to evaluate and rank molecules identified by COSS, providing DART with a short list of de-risked candidates that could be in-licensed.

Like CFIDS, DART is allied with an energized patient population – in its case, the Duchenne's muscular dystrophy (DMD) community, which aggressively searches the scientific literature seeking therapeutic assets that could be repurposed for DMD, explained Gene Williams, DART's executive chairman and CEO. By partnering with Biovista, DART hopes to find the most promising assets.

"We're very happy with where we've gotten so far," Williams told BioWorld Today.

After running COSS for nearly 15 years, Biovista "has developed a very sophisticated tool for generating hypotheses," he added. Although the methodology is essentially the same as a scientist might use to "connect the dots" between a drug's mechanism of action and a disease target before conducting confirmatory research, "COSS does this in a very comprehensive and efficient way."

DART discovered previously unidentified leads in its first COSS run. "More than half of them look extremely interesting," Williams said.

Unmet medical need persists, in part, because animal models are poorly predictive, he pointed out.

"If you have the sophisticated biologic hypothesis that COSS offers and you confirm that with an animal model, you're making a better bet," he said.

Cempra Inc., of Chapel Hill, N.C., forged a similar alliance with Biovista in 2008 to identify and profile adverse event associations for members of the macrolide drug class. At the time, the company was still in preclinical studies and had limited animal toxicology data on lead compound solithromycin (CEM-101), a first-in-class fluoroketolide antibiotic candidate, recalled Prabhavathi Fernandes, Cempra's president and CEO.

The company ran the COSS technology on solithromycin, an analog of telithromycin that does not contain a pyridine in the side chain of the molecule. COSS confirmed that solithromycin was not burdened by the toxicity profile of telithromycin.

"That was positive for us," Fernandes told BioWorld Today. "We moved forward, and we have since shown that solithromycin is superior, without the toxicity of telithromycin."

Although Cempra likely would have reached the same conclusion without COSS, "it did provide us with reassurance," Fernandes said. The finding also helped the company to focus its research and resources. "If the COSS technology had suggested the compound might be toxic, like telithromycin, we might have been a little more worried and looked at some other compounds," she admitted.

Fernandes also praised the technology's ability to identify new potential pathways for existing or failed drugs. "That's going to be the big use of this technology in the future," she predicted.

Biovista has reached the same conclusion. Although the company has its own preclinical drug pipeline, it's beginning to place some of those candidates into virtual newcos while keeping the COSS platform as its star attraction – a canny strategy should its future include a venture financing or public offering.

Because COSS generates revenues from partners, either on a fee-for-service basis or in up-front and milestone payments, Biovista can fund early stage development of drug candidates after their vetting by COSS. The company is currently developing the first two newcos, which could eventually seek their own partners, Persidis said.

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