Officials of Tetraphase Pharmaceuticals Inc. don't know yet if they can salvage enough from the failed phase III trial called IGNITE2 to file for approval of its antibiotic eravacycline, which beat levofloxacin in a subset of patients with infections caused by quinolone-resistant bugs and met its endpoint in an earlier phase III experiment. Neither of these factors did much to satisfy investors, who took down Watertown, Mass.-based Tetraphase (NASDAQ:TTPH) by 78.8 percent Wednesday, the shares closing at $9.49, a loss of $35.29.
CEO Guy Macdonald in a conference call with investors pointed to cases "where the agency has allowed companies to do one trial and others two. So I think clearly the opportunity does exist there, but I think it's down to an individual discussion with the agency to finalize that, which we intend to do once we understand the data."
An acronym for Investigating Gram-Negative Infections Treated with Eravacycline, IGNITE2 tested eravacycline as an intravenous (IV)-to-oral transition therapy for complicated urinary tract infection (cUTI) with a primary endpoint of statistical overall non-inferiority compared to levofloxacin. The first study, IGNITE1, did hit the primary endpoint in complicated intra-abdominal infections, showing high cure rates given as IV in prevalent gram-negative pathogens, as well as a favorable safety profile.
Specifically, the pivotal portion of IGNITE2 enrolled 908 patients randomized 1:1 to get eravacycline (1.5 mg/kg IV every 24 hours followed by 200 mg orally every 12 hours) or levofloxacin (750 mg IV every 24 hours followed by 750 mg orally every 24 hours). Each patient received a minimum of three days of IV dosing and then, if clinically indicated, was eligible to transition to oral therapy for the remaining doses, for a total treatment period of seven days.
The primary analysis for the FDA evaluated the responder outcome (a combination of clinical cure rate and microbiological response) in the microbiological intent-to-treat (micro-ITT) population at the post-treatment (PT) visit (defined as six to eight days after the completion of therapy) using a 10 percent non-inferiority margin. For the EMA, the primary analysis evaluated the microbiological response in the micro-MITT population along with microbiologically evaluable populations at the PT visit, also using a 10 percent non-inferiority margin. Eravacycline fell short in both.
Asked about the dropout rate, Tetraphase's chief medical officer Patrick Horn said the firm is "still in the process of really analyzing all of this data. I think our safety tolerability profile, which includes the discontinuation rate, was similar to what we saw in the lead-in part," where the rate was "very low." Wedbush Securities analyst Heather Behanna wanted to know about the response rates of levofloxacin, if it was similar to the lead-in overall or similar to what we've seen in competitor trials, just so that we can gauge that as a benchmark of performance in the study." But Horn wasn't ready to talk about that either. Almost exactly a year ago, Tetraphase wowed Wall Street with top-line data from the lead-in portion of IGNITE2, showing that the oral and IV doses compared favorably with levofloxacin in cUTI. (See BioWorld Today, Sept. 4, 2014.)
BUSY SPACE AS RESISTANCE GROWS
Aside from eravacycline, Tetraphase has filed an investigational new drug application for TP-271, described as a broad-spectrum antibiotic in the works for respiratory infections caused by bacterial biothreats. The company plans to start a phase I trial in the fourth quarter of this year. Bound for the clinic is another compound, TP-6076, a second-generation candidate for multidrug-resistant, gram-negative pathogens.
Tetraphase ended the second quarter of this year with $242.1 million in cash and equivalents. Before adjusting for expenses related to the IGNITE2 trial results, the firm's current cash on hand plus expected revenue from government grants should be enough to keep going through the first quarter of 2017, according to an estimate by analyst Jonathan Aschoff with Brean Capital LLC. He downgraded his rating of the firm to "hold" from "buy," and noted in a research report that, "given eravacycline's qualified infectious disease product [QIDP] and fast-track status, we believe that Tetraphase will be able to meet with the FDA by the end of this year to discuss next steps."
Taking a broader view, Leerink Partners LLC analyst Paul Matteis in May gave a nod to the bear thesis on "any novel antibiotic play that the availability of cheaper generics minimizes the market for new agents." He predicted that such agents as eravacycline, if they reach the market, would be "reserved for sicker patients for whom the cost/benefit of using a branded agent is clearly favorable. However, the development of antibiotic resistance to over-prescribed generics creates a continuous need for new therapies," and a new drug would only have to capture low-to-mid single-digit share for decent profits, he wrote in a research report.
Matteis covers Boston-based Paratek Pharmaceuticals Inc., which last October completed its reverse merger with Transcept Pharmaceuticals Inc., of Point Richmond, Calif., grossing $93 million in new investment from a combination of some current and new investors. In May of this year, Paratek was able to raise $71.1 million more through a secondary offering. The firm has oral and IV omadacycline for acute bacterial skin and skin structure infections (in phase III trials), community-acquired bacterial pneumonia (CABP, phase III to start this year), with an earlier program in urinary-tract infections. Omadacycline also has QIDP status.
Another contender in the space is Cempra Inc., of Chapel Hill, N.C., with oral and IV solithromycin, which won fast-track designation in August for CABP. Solithromycin is in phase III trials in that indication and a new drug application is planned for next year. The FDA has tagged the drug as a QIDP in CABP and gonorrhea, where it's also in phase III trials.