Following Tuesday's market close, Tetraphase Pharmaceuticals Inc. reported top-line data from the lead-in portion of its two-part phase III IGNITE (Investigating Gram-negative Infections Treated with Eravacycline) 2 trial, showing that both intravenous (I.V.)-to-oral dosing regimens of eravacycline (1.5 mg/kg I.V. followed by 200 mg or 250 mg) compared favorably to comparator drug levofloxacin to treat complicated urinary tract infections (cUTIs). The company said the findings support the trial's advancement into its pivotal stage, expected to begin early in the fourth quarter.
Shares of Tetraphase (NASDAQ:TTPH) popped 13 percent Wednesday morning and finished the day at $15.01 for a gain of $1.93. Volume was more than eight times heavier than usual.
The randomized, double-blind IGNITE 2 trial is assessing the efficacy and safety of eravacycline, formerly TP-434, in cUTI at approximately 150 sites across the globe. The lead-in portion, with approximately 120 patients randomized 1-to-1-to-1, received eravacycline in one of two I.V.-to-oral switch dosing cohorts (1.5 mg/kg intravenously every 24 hours followed by 200 mg or 250 mg orally every 12 hours) or levofloxacin (750 mg intravenously every 24 hours followed by 750 mg orally every 24 hours).
Tetraphase determined the two oral dosing regimens based on a completed phase I oral pharmacokinetic trial of eravacycline that showed acceptable plasma drug levels and tolerability in healthy subjects at the 200-mg and 250-mg twice-daily dose levels.
The evaluation of primary efficacy, safety and tolerability endpoints was conducted as part of a planned interim analysis under the IGNITE 2 protocol following treatment of patients in the lead-in portion. Tetraphase expects to enroll another 720 patients in the pivotal trial, randomized 1-to-1 to the selected dose regimen of eravacycline or levofloxacin, with a goal of showing noninferiority, based on a 10 percent margin. The primary endpoint for the FDA is responder outcome in the microbiological intent-to-treat (micro-ITT) population at the post-treatment visit, six to eight days after completing therapy. For the EMA, the primary endpoint is the microbiological response in the micro-modified ITT (micro-MITT) and microbiologically evaluable populations at the post-treatment visit.
In the lead-in portion, responder outcome in the micro-ITT population – the primary endpoint for regulatory review by the FDA – for the I.V.-to-oral 200-mg, I.V.-to-oral 250-mg and levofloxacin groups was 70.8 percent, 64.3 percent and 52.2 percent, respectively. Microbiological response in the micro-MITT and microbiologically evaluable populations – the primary endpoint for review by the EMA – was 75 percent, 64.3 percent and 56.5 percent for the three dose cohorts, respectively.
Tetraphase said the pharmacokinetics of both oral doses of eravacycline were comparable to the I.V. formulation. Overall, treatment was well tolerated in all three groups, with nausea and emesis reported as the most common adverse events. Two patients – one in the eravacycline arm and one in the levofloxacin arm – discontinued treatment due to drug-related adverse events.
Tetraphase just wrapped up the phase III IGNITE 1 study evaluating the I.V. formulation of eravacycline in complicated intra-abdominal infections (cIAIs), but "this is the first time that we've treated patients with the I.V.-to-oral transition therapy," said Guy Macdonald, president and CEO of the Watertown, Mass.-based company. "Clearly, it's working."
Only one new compound in the tetracycline class, Tygacil (tigecycline, Pfizer Inc.), has been approved in more than 30 years, mainly because semisynthetic production methods hinder chemical diversity. With eravacycline – a fully synthetic tetracycline licensed from Harvard University – entering its final lap, Tetraphase aims to change that. The compound has shown activity against a broad spectrum of bacteria, including multidrug-resistant (MDR) gram-negative, gram-positive and anaerobic bacteria.
'WE'VE GOT SOME GOOD MILESTONES COMING UP'
The Generating Antibiotic Incentives Now (GAIN) provision in the FDA Safety and Innovation Act, passed in 2012, smoothed the regulatory pathway for antibiotics developers, enabling Tetraphase to design a phase III program using one study in cIAI and one in cUTI, rather than two studies for each infection, as would be necessary for complicated skin infections or pneumonia. (See BioWorld Today, Oct. 2, 2013.)
The fact that relatively few broad-spectrum antibiotics in development have shown efficacy in both I.V. and oral formulations is a differentiator for Tetraphase, according to Macdonald.
"It's very important for us, and very exciting," he said.
Macdonald said Tetraphase will disclose additional detail from the lead-in portion and confirmation of the oral dose selected for the pivotal portion of IGNITE 2 after sharing the data with the FDA, as agreed during previous discussions with the agency. Tetraphase plans to present full data from the lead-in portion of the phase III study at an undisclosed scientific meeting.
The lead-in data provide a benchmark for the pivotal portion of IGNITE 2, not only in terms of efficacy but also in recruitment trends. Tetraphase opened 70 sites for the lead-in portion – though only half that many were needed – to ready them for the pivotal phase. Another 75 are being opened while the company completes its review of the top-line data.
"We've got some really good insight now from the sites that have been recruiting and the data so far," Macdonald told BioWorld Today. "We hope to replicate the safety and efficacy data."
Neighboring Cubist Pharmaceuticals Inc., of Lexington, Mass., also used noninferiority with levofloxacin as the primary endpoint in its pivotal phase III trial of antibiotic candidate ceftolozane/tazobactam (CXA-201) in cUTI and cIAI. That compound, which pairs an agent from the cephalosporin class with a beta-lactamase inhibitor, blasted past expectations in the modified ITT population, showing a composite cure rate of 60 percent vs. 39.3 percent against levofloxacin-resistant pathogens and 62.3 percent vs. 35.1 percent against extended-spectrum beta-lactamase-producing pathogens Escherichia coli and Klebsiella pneumonia. (See BioWorld Today, May 13, 2014.)
"Cubist was able, in a large population, to show superiority in the levofloxacin-resistant population, and we obviously hope to be able to do the same thing, which is something we did not intend to do in the earlier part of our study," Macdonald said.
Clearing that bar certainly seems within reach, according to Brean Capital LLC analyst Jonathan Aschoff, who observed in a company update that the interim phase III data in cUTI demonstrated eravacycline's effectiveness, even though the lead-in portion was not powered to show statistical significance.
Findings from the IGNITE 1 study of I.V. eravacycline in cIAI represent the next milestone for Tetraphase. The company rolled the last patient off that study just last week "so we're now going to tidy up that database and expect to report data early next year," Macdonald said.
Findings from the pivotal portion of IGNITE 2 are slated to report by mid-2015.
Thanks to its 2013 initial public offering, which grossed $80.6 million, including overallotments, and funding from the Biomedical Advanced Research and Development Authority, Tetraphase has a comfortable runway through the end of next year. (See BioWorld Today, Feb. 13, 2013, and March 21, 2013.)
"We are having discussions with people to see what makes sense in terms of ex-U.S. partnering," Macdonald said. "Beyond that, we'll be opportunistic about what makes sense in terms of financing. Clearly, we've got some good milestones coming up that will allow us to do that."