Key findings include:
- A once-daily tablet of tedizolid, given over six days, is as effective as a Zyvox (linezolid) tablet given twice a day for 10 days.
- This is the first published Phase 3 study under new FDA draft guidelines for acute bacterial skin and skin structure infections (ABSSSI), which call for evaluating a response to antibiotics two-to-three days after starting treatment.
- Response was seen in two to three days, which was a strong predictor of outcomes at the end of therapy (day 11). The study validates the FDA’s early endpoint guidance, which could help address this challenge cited in the paper: “…contemporary clinicians often wait for more clinical information to become available before concluding the [antibiotic's] outcome as favorable or unfavorable, leading to unnecessary and prolonged hospitalization or inappropriate use of antibiotics.”
Trius Therapeutics, Inc. (Nasdaq:TSRX), a biopharmaceutical company focused on the discovery and development of innovative antibiotics for serious infections, have announced that the results from ESTABLISH 1, a Phase 3 study of tedizolid phosphate (TR-701) versus linezolid (Zyvox®) completed in 2011, have been published in The Journal of the American Medical Association (JAMA).
The ESTABLISH 1 trial examined the efficacy and safety of a 200 mg tablet of tedizolid given once a day for six days versus a 600 mg tablet of linezolid given twice a day for 10 days in 667 patients in North America, Latin America and Europe. The trial was the first pivotal study conducted to prospectively measure the new FDA “early response” primary endpoint of cessation of lesion spread and absence of fever 48-72 hours after the first dose. The trial also measured as secondary endpoints this “early response” sustained to the end of therapy (EOT; day 11) as well as captured the EMA endpoint of clinical investigator’s assessment at the post-treatment evaluation visit (7-14 days after EOT).
As detailed in the JAMA article, tedizolid achieved the primary and all secondary endpoints in the ESTABLISH 1 trial. Approximately 42 percent of pathogens isolated at baseline in the study were methicillin resistant Staphylococcus aureus (MRSA). For both tedizolid and linezolid there was good concordance ( > 80%) between the early primary endpoint and late investigator assessed secondary endpoints suggesting that the early response is a good indicator of a sustained clinical response to therapy. In addition, the trial showed that tedizolid had a statistically lower impact on platelets and was associated with a statistically significant lower rate of gastrointestinal (GI) adverse events than linezolid.
“While being the pioneer on a pivotal study conducted under new guidance offers many challenges, the results speak for themselves and are a testimony to the extraordinary efforts of the Trius team working in concert with the FDA,” said Philippe Prokocimer, M.D., Chief Medical Officer at Trius and lead author of the JAMA article. “Publication of the ESTABLISH 1 trial results in JAMA further confirms the need for new antibiotics such as tedizolid.”
In an accompanying editorial in the JAMA issue, Drs. Shira Doron and Helen Boucher state, “Much can be learned from the current study about the appropriate use of antibiotics for the treatment of these common infections, and the design of future trials for treatment of ABSSSI.” They also highlight that “Tedizolid is a new oral antibiotic that appears efficacious using a short course of therapy and may have a better safety profile than linezolid.”
In December 2012, Trius announced that it completed enrollment of its second ABSSSI trial, ESTABLISH 2. This second pivotal Phase 3 trial was designed to evaluate the efficacy and safety of tedizolid and linezolid when initially administered as an intravenous (IV) infusion with the option to switch to oral therapy. Trius expects to report top-line results from the ESTABLISH 2 study around the end of the first quarter of this year.