Promising Broad-Spectrum Antibiotic Offers Coverage of Most Serious Pathogens

Alice Goodman

September 16, 2010

September 16, 2010 (Boston, Massachusetts) — The investigational broad-spectrum antibiotic TP-434 (Tetraphase Inc) holds promise as a broad-spectrum antibiotic for treating serious infections in hospitalized patients, according to preliminary data from a number of posters presented here at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

The investigational broad-spectrum fluorocycline is in the early stages of development as an intravenous (IV) antibiotic with broad coverage of Gram-negative, Gram-positive, aerobic, anaerobic, and atypical organisms responsible for serious infections. Tetraphase plans to have a companion oral formulation of the drug as well.

While acknowledging that these data are potentially exciting, experts cautioned that enthusiasm should be tempered until phase 3 studies are conducted.

"TP-434 nails the most troublesome hospital pathogens [with the exception of Pseudomonas aeruginosa] with very little compound" — the minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC90) is 0.012 μg/mL — reported Joyce Sutcliffe, PhD, who was lead author of 2 of the posters and coauthor of the third one. Dr. Sutcliffe is senior vice president of Tetraphase in Watertown, Massachusetts.

The novel compound is a fully synthetic tetracycline derivative. "Tetracycline has long been known to have oral and IV advantages. We have revitalized tetracycline to develop TP-434," she said. The novel compound is not subject to forms of resistance due to extended-spectrum beta lactamases or carbapenamases, she added.

The first poster presentation showed that TP-434 was 4 times more active in vitro than tigecycline against the anaerobic Bacteroides organisms and against Providencia, Morganella, and Proteus sp.

The second poster demonstrated the activity of TP-434 against most serious pathogens in murine models. TP-434 was 3 to 5 times more potent than tigecycline against Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA), and 3 to 5 times more potent than vancomycin against MRSA, Dr. Sutcliffe explained.

The third poster was of a phase 2 standard-ascending-dose study of 7 different doses of TP-434 in 56 subjects. The objective was to assess safety, tolerability, pharmacokinetics, and pharmacodynamics. Four cohorts of 8 subjects each had multiple ascending doses (6 on drug and 2 on placebo at each dosing level).

Two different doses of the IV drug were chosen to take forward in phase 2 trials: 8,600 ng × h/mL and 13,000 ng × h/mL. The normal dose of tigecycline is 4,700 mg × h/mL.

"Better exposure [than tigecycline] leads to better efficacy, particularly against Gram-negative organisms that have a high MIC90," Dr. Sutcliffe explained.

She added that an oral phase 1 single-ascending-dose study (not ready in time for ICAAC) demonstrated area under the curves consistent with therapeutic coverage, offering potential for IV to oral step-down treatment with TP-434, which will be a major advantage for this drug.

"Instead of 14 days in the hospital for a serious intra-abdominal, skin, or pneumonia infection, patients can be sent home earlier on an oral medication. No other broad-spectrum antibiotic for this use has an oral formulation, except the fluoroquinolones, which have been plagued by resistance," she said.

Caution Advised; Results Are Preliminary

"This drug looks good on paper," said Karen Bush, PhD, adjunct professor of biology at Indiana University in Bloomington. "Safety will be the biggest issue, as a safety concern has been raised with tigecycline."

If the clinical trials turn out to be positive, she added, this will be a drug that meets a serious medical need to hit resistant Gram-negative organisms, including those that produce New Delhi metallo-beta-lactamase 1 (NDM-1).

Medscape Medical News has published a number of reports recently on NDM-1, including a look at the contribution NDM-1 to antibiotic resistance.

Although promising, these data are very preliminary, cautioned Vance Fowler, MD, from Duke University in Durham, North Carolina.

"The data sound good, but communism sounds good too. These studies show proof of principle to take the drug to the next stages of development and confuse the issue with facts," Dr. Fowler stated somewhat facetiously.

Dr. Sutcliffe is an employee of Tetraphase, Inc. Dr. Bush reports financial ties with Johnson & Johnson, Wyeth (now Pfizer), BMS, Cubist, and Merck. Dr. Fowler reports receiving financial support from Astellas, Cubist, Merck, Theravance, Cerexa, Pfizer, Novartis, Inhibitex, Arpida, Targanta, Wyeth, Ortho-McNeil, Vertex Pharmaceuticals, Leo Pharmaceuticals, NovaDigm, The Medicines Company, Baxter Pharmaceuticals, Biosynexus, and Johnson & Johnson.

50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstracts F1-2157 and F1-2158; presented September 12, 2010. Abstract A1-027; presented September 15, 2010.


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