Two phase III stumbles of Iterum Therapeutics plc’s sulopenem have cast the company’s future in doubt.

The latest problem is the failure of the penem anti-infective compound, with oral and I.V. formulations, failing to achieve statistical noninferiority relative to ertapenem in treating complicated urinary tract infection (cUTI). The primary endpoint for the SUlopenem for Resistant Enterobacteriaceae, or SURE 2, trial was overall clinical and microbiologic response on day 21 in the micro-modified intent-to-treat (micro-MITT) population as evaluated using a 10% noninferiority margin.

The company stock (NASDAQ:ITRM) was punished for the failure, with shares plummeting 59.6% on June 1 to close at $1.70 each.

The SURE 2 study had enrolled 1,395 adults to measure the efficacy, tolerability and safety of I.V. and oral sulopenem for treating cUTI. Randomized patients received I.V. sulopenem once daily for a minimum of five days followed by oral sulopenem twice daily for 10 days or I.V. ertapenem once daily for a minimum of five days, followed by either oral ciprofloxacin or, for quinolone-resistant isolates, amoxicillin-clavulanate twice daily.

Responder rates at the test-of-cure visit for sulopenem were 67.8% (301 of 444 patients) and for ertapenem were 73.9% (325 of 440 patients) with a difference of -6.1% (95% confidence interval (CI): -12%, - 0.1%). The difference in response rates was driven almost entirely by higher rates of asymptomatic bacteriuria on sulopenem relative to ertapenem, the company said. The rates of patients receiving additional antibiotics or with residual cUTI symptoms was similar.

In early December, Iterum, of Dublin and Chicago, posted less-than-stellar results from its phase III trial called SURE 3, testing oral and I.V. versions of the drug in complicated intra-abdominal infections. The stock slid 36% that day.

SURE 3 compared I.V.-to-oral sulopenem-probenecid vs. I.V. ertapenem (Ivanz, Merck & Co. Inc.) followed by oral ciprofloxacin plus oral metronidazole. The primary endpoint was clinical response on day 28 in the micro-MITT population. Difference in outcomes turned up at 4.7% with a 95% confidence interval of -10.3% to 1%. Noninferiority to the comparator ertapenem, as decreed by the FDA, required that the lower limit of the difference in the outcome rates be 10% or less.

Data from a third phase III study, SURE 1, have yet to arrive. Near December’s end, when the company said it had completed enrollment for SURE 1 in uncomplicated urinary tract infections (uUTI), hope for the company was apparent as share prices rose 95% to $4.75 on Dec. 27.

Iterum said on May 14 that it expected top-line results from the uUTI trial “shortly thereafter within the second quarter.”

Expectations for the UTI trials were high. H.C. Wainwright analysts wrote on May 14 that they expected “positive data from these trials to enable sulopenem's NDA filings in 2H20.” SVB Leerink analysts wrote Monday the cUTI indication had contributed to slightly more than 50% of its revenue forecast for Iterum.

Iterum’s loss may be Spero Therapeutics Inc.’s gain, as the Cambridge, Mass.-based company has a pivotal phase III in cUTI underway. Top-line data are expected in the third quarter of 2020 for tebipenem HBr, an oral formulation of tebipenem pivoxil, a carbapenem-class antibiotic, for treating cUTI and acute pyelonephritis. The study of more than 1,370 eligible subjects is a double-blind, double-dummy trial comparing an all-oral regimen of tebipenem HBr dosed as 600 mg three times daily with a standard-of-care I.V. antibiotic, ertapenem, randomized 1-to-1 in each arm.

Spero stock (NASDAQ:SPRO) rallied 9.64% on June 1, with shares closing at $12.96. Those same shares sold for $5.27 each on March 16 and have climbed steadily since.

Iterum’s management said it is considering its options, including the licensing, sale or divestiture of the company’s assets or proprietary technologies, a sale of the company, a merger or other business combination, another strategic transaction involving the company, restructuring activities, winding down of operations, dissolving and liquidating assets or seeking protection under bankruptcy laws.

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