Sulopenem / ORLYNVAH approved for uUTI
When Iterum, a Pfizer spin-off of sorts, took over sulopenem development in 2015, there was still hope for approvals of this drug in multiple indications such as uUTI, cUTI, cIAI and even CABP. Ten years later and after an FDA rejection CRL in 2021, the drug was finally approved in 2024, alas for only one indication: uUTI. In addition, the label came with considerable restrictions addressing FDA concerns about potential resistance development following indiscriminate oral penem use in the community setting[1],[2]. Fallen by the wayside are IV formulation and IV/PO step-down for which development has stopped.
Pfizer probably anticipated this outcome long time ago when it shelved the drug before Iterum resurrected it. Is this a case of too little too late?
Half a year after approval of sulopenem etzadroxil and probenecid, ORLYNVAH is still not commercially available. Iterum is looking for a strategic partner with the Sales & Marketing muscle to introduce ORLYNVAH in a market where cheap generic alternatives are plentiful and well established. It does not take an MBA degree to understand the dilemma: while the uUTI market is large, only a small fraction of these patients will be candidates for sulopenem; pricing pressures stand to relegate ORLYNVAH to 3rd or 4th tier choice.
This is a deja-vue all over again, and it reminds us of the fate of Achaogen and plazomicin/ZEMDRI. That company, ill-advised by the FDA, went bankrupt shortly after declaring approval victory.
This blog could just stop here, as the development story of sulopenem is somewhat boring. Its downhill path is paved with failed trials; for the interested reader, we refer you to the publications of the cUTI, cIAI and uUTI (cipro-susceptible subpart) trials[3],[4],[8].
It all reminds us of our own experience with faropenem, another oral penem which was developed by Bayer, later by Replidyne, 20 years ago. A large multi-indication program was successfully executed following then-existing FDA guidelines, but the Agency changed the rule book and called the entire program unapprovable. FDA simply declared that ‘the science had changed’ but had no new guidances to replace the old ones[5]. The mess created by such regulatory uncertainty made many companies decide to leave the field of antibacterials. Replidyne ceased to exist. We refer you to the status of the antibacterial pipeline in a recent blog.
Of moderate interest perhaps, the FDA ultimately approved the uUTI indication based on evidence from a single trial, the REASSURE trial, a well-designed, large study (2214 adult women). They accepted circumstantial evidence of efficacy from other sources[6],[7].
FDA has shown some flexibility in recent years regarding the dogma of 2 mutually confirmatory pivotal studies. In the case of sulopenem, a drug, which is already proven safe, comes from a well-known drug class (beta-lactams), and for which rather large datasets are available, the regulatory risk was miniscule.
Let’s clear up the controversial issue of efficacy in the first uUTI trial (SURE-1) as claimed by Iterum[8]. Technically speaking, efficacy was only seen in the cipro-resistant subgroup, but non-inferiority was missed for the primary endpoint in the larger cohort of cipro-susceptible uropathogens.
However, the FDA played it by the book in 2021 and gave Iterum a rough deal. In this well-designed and large (1,670 uUTI patients) SURE-1 trial, ORLYNVAY missed the NI delta of 10% only because of a minor detail: the difference in failure rates which was driven by a rather arbitrary microbiological criterium, a colony count of <1,000 CFU/mL) at TOC in asymptomatic patients.
This cut-off is clinically totally irrelevant; a seasoned reviewer could have dismissed and overridden this minor imbalance. Instead, FDA stuck by numbers and statistics, demanding another uUTI trial which eventually proved the obvious. This decision delayed approval by 4 years and reduced the commercial value while costing the company a huge amount of money. No Fast Track or QIDP label or Expedited Review can ever make up for this commercial delay.
Superiority was shown only in the cohort of cipro-resistant patients, as one would expect. For good reasons, study entry criteria are meant to level the playing field between comparators. Only patients with pathogens susceptible to both study drugs are supposed to be included in the evaluable micro-MITT population. Of course, any comparison of antibiotics with different susceptibility profiles will show superiority for the subset of pathogens susceptible to only 1 but not both antibiotics . It’s the microbiology that matters – we discussed this in a recent blog on gepotidacin.
As it stands, it is difficult to see how the drug can become commercially successful. By comparison, gepotidacin is a shining star with the benefit of 2 indications (uUTI and uGC) and a novel MoA. ORLYNVAH only proved NI against decades-old amoxiclav, not exactly a high threshold of activity. In former years, FDA would have called this kind of comparator a case of ‘biocreep’.
Infectious disease specialists are always on the lookout (and like to publish!) the first cases of resistance once a new drug is released. The claim that resistance development with ORLYNVAH is less likely to happen as it requires 2 separate mutations should be considered a ‘Forward Looking Statements” piece for investors. We heard similar claims before, which did not hold up long.
We beg to differ with the assessment of various experts touting the ‘medical need’ for sulopenem in uUTI. The ‘medical need’ moniker is being used quite loosely in general. Every resistant bug represents a case of ‘medical need’, even in uUTI. But the availability of several treatment options for ‘resistant’ isolates such as nitrofurantoin makes the ‘medical need’ argument somewhat unconvincing.
ORLYNVAH is meant for patients who have “limited or no alternative oral antibacterial treatment options”. With many older drugs still being quite efficacious, and several very inexpensive options even for more resistant bugs, where is the market?
One capsule of sulopenem-etzadroxil plus probenecid, 500 mg each, will have to be large, probably triple-000 format. This is a big pill to swallow, even if only for 5 days. But gepotidacin pills are also big and must be taken as 2 pills BID. The market will determine which one of these newer uUTI drugs will ultimately prevail.
Iterum is a Latin word and means ‘again’. Indeed, the drug survived an earlier FDA rejection and re-emerged in 2025, but this is not a ‘Phoenix rising from the ashes’ story: regrettably, this bird has lost too many feathers…
ABBREVIATIONS
CABP community-acquired (bacterial) pneumonia
cIAI complicated intra-abdominal infection
CRL complete response letter (FDA)
EOT end-of-treatment timepoint
micro-MITT modified intent-to-treat population AND valid uropathogen
NI non-inferiority margin (delta)
QIDP qualified infectious disease product
TOC test-of-cure timepoint
uGC uncomplicated gonorrhea
REFERENCES
[1] Sulopenem / ORLYNVAH Package Insert 2024
[2] FDA Integrated Review, NDA 213972 (Sulopenem etzadroxil/probenecid) 2024
[3] Dunne M. Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial. Clin Infect Dis 2023;76:78
[4] Dunne M. A phase 3 randomized trial of sulopenem vs. ertapenem in patients with complicated intra-abdominal infections. Clin Microbiol Infect. 2025;31: 396
[5] Schurek K. Faropenem: review of a new oral penem. Expert Rev Anti Infect Ther . 2007; 5:185
[6] FDA Guidance for Industry Uncomplicated Urinary Tract Infections: Developing Drugs for Treatment (August 2019)
[7] Puttagunta S. P-1107. Oral Sulopenem/probenecid for Uncomplicated Urinary Tract Infections (uUTI): Results from the REASSURE Trial. Open Forum Infect Dis. 2025;12 (Suppl 1): ofae631.1295
[8] Dunne M. LB-1. Efficacy and Safety of Oral Sulopenem Etzadroxil/Probenecid Versus Oral Ciprofloxacin in the Treatment of Uncomplicated Urinary Tract Infections (uUTI) in Adult Women: Results from the SURE-1 Trial. Open Forum Infect Dis. 2020;7 (Suppl 1): S844
