April 15, 2012 (Vol. 32, No. 8)

Trius Therapeutics’ Second-Generation Oxazolidinone Targeted at MRSA

New antibiotics are desperately needed to treat serious drug-resistant gram-positive bacterial infections, such as methicillin-resistant Staphylococcus aureus (MRSA), which place an increasing burden on healthcare resources. To address this need, Trius Therapeutics is testing a second-generation oxazolidinone antibiotic, called tedizolid phosphate, in Phase III clinical trials. Pfizer’s Zyvox® (linezolid) is a first-generation oxazolidinone approved to treat MRSA, and it is the only marketed oxazolidinone.

Previous clinical and nonclinical testing showed that tedizolid has better potency and safety profiles than Zyvox, according to Trius. In fact, the firm claims that tedizolid is four to eight times more potent than Zyvox against both MRSA and vancomycin-resistant enterococci. Other advantages Trius notes for tedizolid include highly efficient oral absorption, rapid in vivo bactericidal activity, and once-daily oral or intravenous (IV) administration. Hospitalized patients treated with the IV drug can be transitioned to the oral form when they are discharged from the hospital.

“It’s unusual in the antibacterial marketplace to have only one member of a drug class,” says Jeffrey Stein, Ph.D., president and CEO. Starting in 2005, Dr. Stein searched worldwide for 18 months to find antibacterial compounds with compelling preclinical efficacy and safety data. He discovered tedizolid at Dong-A Pharmaceutical in South Korea and licensed the compound in 2007.

A Phase I trial in 2008 conducted by Trius compared tedizolid to Zyvox and the results confirmed the potential of Trius’ new drug, Dr. Stein reports. “We were prepared to terminate the development of tedizolid if it did not demonstrate a potential safety advantage over Zyvox in this 21-day study,” he says.

Trius Therapeutics is carrying out IND-enabling studies for its Gyrase-B development candidate with activity against gram-negative bacterial pathogens including multidrug resistant strains of E. coli (shown here), Klebsiella, Acinetobacter, and Pseudomonas.

Selective Modifications

Oxazolidinones are small molecule drugs that bind to 23S ribosomal RNA in a specific location and inhibit protein translation. Unlike Zyvox, tedizolid lacks an acetamide group, long assumed to be essential for oxazolidinones to bind to their targets. Strains of MRSA become resistant to oxazolidinones due to mutations at the acetamide site.

“Eliminating the acetamide group minimizes the ability of pathogens to evolve resistance mutations,” says Dr. Stein. Pathogens become resistant to tedizolid 10 times more slowly than to Zyvox, he remarks.

Scientists at Dong-A made tedizolid even better by replacing the acetamide group with a smaller hydroxy methyl group and then adding a phosphate. This makes tedizolid a highly soluble, yet inactive prodrug. The body’s natural serum phosphatases cleave the phosphate ester bond, releasing a highly soluble and active molecule. The highly soluble phosphate group also allows for IV formulation and improves oral bioavailability.

In general, when oxazolidinones are modified to improve potency, they become less soluble and more difficult to formulate as IV drugs. The Korean scientists found “a very clever solution to a problem facing those trying to develop second-generation oxazolidinones,” says Dr. Stein.

Trius Therapeutics announced results of its Phase II trial in June 2009. Patients with complicated skin infections were treated orally with tedizolid for five to seven days. The overall cure rate was 98% for the 200 milligram dose, and patients with MRSA skin infections had a 100% cure rate.

Trius is running two Phase III trials. Top-line data from the first Phase III trial was released in December 2011. The primary endpoint of efficacy noninferiority to Zyvox was met, and noninferiority for safety was also demonstrated, Dr. Stein reports. The second trial is an IV-to-oral transition study, which is still ongoing.

Marine Microbes Next

The preclinical program at Trius focuses on GyrB and ParE, both targets of gram-negative bacteria. GyrB and ParE are needed for DNA replication. They are part of macromolecular complexes that are targeted by the well-known quinolone class of antibiotics. “Our GyrB compounds are hitting the same macromolecular targets as quinolones, but at different binding sites. This makes our lead compounds active against quinolone-resistant pathogens,” says Dr. Stein.

Trius researchers engineered compounds with broad-spectrum activity against gram-negative pathogens like Pseudomonas and Klebsiella as well as gram-positive pathogens like MRSA. A lead series of compounds show good potency in animal efficacy studies, Dr. Stein reports. “This could be the first truly novel class of broad-spectrum antibiotics that are active against all known resistant strains,” he says.

A second preclinical program focuses on a collection of molecules being developed at the Scripps Institute of Oceanography. The antimicrobial agents are derived from marine strains of Streptomyces, a common soil microbe and previously a rich source of antibiotics. However, “Streptomyces in soil has been tapped out with respect to chemical diversity,” says Dr. Stein. The Scripps scientists discovered marine strains with complex metabolic processes and novel chemical diversity. They are screening libraries to identify candidates with potent antimicrobial activity.

Trius Therapeutics benefits from a two-tiered funding structure. The development of tedizolid is backed by private and public investors, whereas federal grants support investigations of the early-stage broad-spectrum antibiotics and marine microorganisms.

The National Institute of Allergy and Infectious Diseases has awarded Trius $27.7 million, and the Defense Threat Reduction Agency has given $29.5 million to identify and develop novel antibiotics or countermeasures for biodefense threats.

“With this structure, our investors’ dollars are focused on our late-stage programs. Yet they can benefit from the potential upside of our early-stage programs if any of them progress into the clinic,” says Dr. Stein.

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