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Recent trends in medical audits and what physicians can expect with the CMS changes in 2021 to the documentation of E/M codes.



Trends in coding audits and what physicians can expect

The FDA has accepted a Biologics License Application (BLA) seeking approval of nivolumab (Opdivo) co-formulated with Halozyme’s proprietary recombinant human hyaluronidase (rHuPH20), or subcutaneous nivolumab, for the treatment of patients with all previously approved solid tumor indications for nivolumab as a monotherapy, monotherapy maintenance following completion of combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Nivolumab is currently approved under several indications, including in combination with ipilimumab for the first-line treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), in combination with cabozantinib for the first-line treatment of patients with advanced RCC, for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy, and in combination with cisplatin and gemcitabine for the first-line treatment of patients with unresectable or metastatic urothelial carcinoma.

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024.

 According to a news release from Bristol Myers Squibb,

 approval of the formulation would make it the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in the news release.

 “Opdivo is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV Opdivo but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30-to-60-minute infusion.”

The BLA submission is supported by findings from the phase 3 CheckMate-67T trial (NCT04810078), in which subcutaneous nivolumab met the study’s co-primary end points by demonstrating noninferiority to intravenous (IV) nivolumab regarding time average nivolumab serum concentration over 28 days (C

; geometric mean ratio [GMR}, 2.098; 90% CI, 2.001-2.200) and minimum serum concentration at a steady state (C

Data from the study, which were presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California,

 also showed that subcutaneous nivolumab demonstrated noninferiority to IV nivolumab in the key powered secondary end point of objective response rate (ORR). Specifically, the subcutaneous arm demonstrated an ORR of 24.2% (95% CI, 19.0-30.0) per blinded independent central review (BICR), compared with 18.2% (95% CI, 13.6-23.6) in the IV arm.

The safety profile for subcutaneous nivolumab was consistent with that of the IV formulation. Among patients who received the subcutaneous formulation, 8.1% experienced injection-site reactions, with all being low-grade and transient. Deaths due to study drug toxicity occurred in 3 patients in the subcutaneous arm and 1 patient in the IV arm. Most deaths that occurred during the study were due to disease progression.

In total, the phase 3, open-label CheckMate-67T trial enrolled 495 patients with advanced or metastatic ccRCC who had received prior systemic therapy. Patients were randomly assigned 1:1 to receive 1200 mg subcutaneous nivolumab plus rHuPH20 every 4 weeks (n = 248) or to 3 mg/kg IV nivolumab every 2 weeks (n = 247) for up to 2 years of treatment or until disease progression, unacceptable toxicity, withdrawal, or death.

The co-primary pharmacokinetic end points for noninferiority testing were C

 of subcutaneous nivolumab vs IV nivolumab. The key secondary end point was ORR per BICR.

Final completion of the CheckMate-67T study is expected in January 2026.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 7, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

2. Bristol Myers Squibb announces updated action date by the U.S. Food and Drug Administration for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Published online and accessed May 21, 2024. https://investors.bms.com/iframes/press-releases/press-release-details/2024/Bristol-Myers-Squibb-Announces-Updated-Action-Date-by-the-U.S.-Food-and-Drug-Administration-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

3. George S, Bourlon TB, Chacon MR, et al. Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. 

4. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Last updated March 1, 2024. Accessed May 7, 2024. https://clinicaltrials.gov/study/NCT04810078

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024. 

News

FDA accepts BLA for subcutaneous nivolumab in solid tumors

Findings from an analysis of the phase 3 CheckMate 9ER trial (NCT03141177) presented during the 

 showed that patients with advanced renal cell carcinoma (RCC) who received frontline nivolumab (Opdivo) plus cabozantinib (Cabometyx) achieved a 1.5-times longer mean time surviving treatment-free before the initiation of second-line therapy vs those who received sunitinib (Sutent).

Over the 48-month period following random assignment, patients in the intention-to-treat (ITT) population who received the combination (n = 323) experienced a mean treatment-free survival (TFS) of 7.0 months compared with 4.6 months in the sunitinib arm (n = 328), for a difference of 2.4 months (95% CI, 0.8-3.9). Patients without a grade 2 or higher treatment-related adverse effect (TRAE) experienced a mean TFS of 3.0 months vs 2.3 months, respectively. Those who experienced a grade 2 or higher TRAE experienced a mean TFS of 3.9 months vs 2.3 months. The 48-month mean overall survival (OS) was 35.1 months in the doublet arm vs 30.7 months in the sunitinib arm. The mean times on protocol treatment were 22.6 months compared with 14.1 months, respectively.

Additionally, the 48-month OS rates were 49.2% in the nivolumab plus cabozantinib arm vs 40.2% in the sunitinib arm, and the 48-month TFS rates were 33.3% compared with 12.9%, respectively.

“There are multiple immunotherapy-based combination treatments with similar efficacies approved for first-line treatment of advanced RCC. Therefore, it’s important to characterize patient survival time after treatment initiation,” Charlene Mantia, MD, a medical oncologist at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School in Boston, Massachusetts, said during a presentation of the findings. “Over the 4-year period since first-line protocol therapy initiation, [patients treated with] nivolumab plus cabozantinib achieved a 1.5-times longer mean TFS vs sunitinib.”

CheckMate 9ER was an open-label study that enrolled patients with histologically confirmed untreated advanced or metastatic clear cell RCC who did not receive prior systemic therapy for RCC. However, treatment with 1 prior adjuvant or neoadjuvant therapy was permitted for patients with completely resectable disease if the agent was not VEGF-targeted and if recurrence occurred at least 6 months following treatment.

Patients were randomly assigned 1:1 to receive intravenous nivolumab 240 mg every 2 weeks in combination with oral cabozantinib 40 mg daily or sunitinib 50 mg daily for 4 weeks in 6-week cycles. Treatment in both arms continued until disease progression or unacceptable toxicity, and the maximum duration of nivolumab therapy was 2 years.

The primary end point was progression-free survival by blinded independent central review per RECIST 1.1 criteria. Secondary end points included OS, objective response rate, and safety.

In the ITT population, the baseline characteristics were well balanced between the combination and sunitinib arms; the median age was 62 years (range, 29-90) vs 61 years (range, 28-86), respectively. Most patients in both arms were not from North America or Europe (51.1% vs 50.9%), had a Karnofsky performance status (KPS) of 90 or 100 (79.6% vs 73.5%), underwent prior nephrectomy (68.7.% vs 71.0%), and had tumors without sarcomatoid features (89.1% vs 87.1%).

Additional findings from the TFS analysis showed that patients with IMDC favorable-risk disease in the combination (n = 74) and control (n = 72) arms achieved a 48-month mean TFS of 6.1 months vs 4.3 months, respectively, for a difference of 1.8 months (95% CI, –1.1 to 4.6). The mean OS during this time frame was 38.2 months in the nivolumab plus cabozantinib arm vs 38.6 months in the sunitinib arm. Patients spent a mean time of 25.2 months vs 19.9 months on protocol treatment, respectively.

Further, patients with IMDC intermediate- or poor-risk disease in the combination (n = 249) and sunitinib (n = 256) arms achieved a 48-month mean TFS of 7.2 months vs 4.7 months, respectively, for a difference of 2.5 months (95% CI, 0.8-4.3). The 48-month mean OS was 34.2 months vs 28.5 months, respectively, and patients spent a mean time of 21.8 months in the combination arm vs 12.5 months in the sunitinib arm on protocol treatment.

Results from a TFS subgroup analysis showed that the benefit with nivolumab plus cabozantinib vs sunitinib was observed across prespecified subgroups. The largest differences in 48-month mean TFS in favor of the combination were reported among patients with a KPS of 80 or less (5.3 months [95% CI, 2.1-8.5]), IMDC poor-risk disease (4.0 months [95% CI, 0.5-7.5]), and a PD-L1 expression of at least 1% (3.5 months [95% CI, 0.8-6.1]).

“Mean TFS differences were similarly longer for nivolumab plus cabozantinib vs sunitinib across most baseline subgroups analyzed,” Mantia said in conclusion. “TFS was more frequently observed after patients stopped therapy due to adverse effects, study drug toxicity, or prespecified other reasons with nivolumab plus cabozantinib vs sunitinib. We believe that future studies should continue to investigate the impact of having a defined treatment duration for patients. This partitioned OS analysis highlights important aspects of patient survival time that can be considered in making decisions when choosing a first-line treatment for patients.”

1. Mantia C, Jegede O, Viray H, et al. Partitioned overall survival: Comprehensive analysis of survival states over 4 years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma (aRCC). J Clin Oncol 2024;42(suppl 16):4507. doi:10.1200/JCO.2024.42.16_suppl.4507

2. Powles T, Burotto M, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024;9(5):102994. doi:10.1016/j.esmoop.2024.102994

3. A study of nivolumab combined with cabozantinib compared to sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 9ER). ClinicalTrials.gov. Updated January 17, 2024. Accessed June 4, 2024. https://clinicaltrials.gov/study/NCT03141177

“Over the 4-year period since first-line protocol therapy initiation, [patients treated with] nivolumab plus cabozantinib achieved a 1.5-times longer mean TFS vs sunitinib," says Charlene Mantia, MD. 

Nivolumab plus cabozantinib extends treatment-free survival vs sunitinib in aRCC

The FDA's Antimicrobial Drugs Advisory Committee met on September 9, 2024 to discuss the submitted new drug application (NDA) for sulopenem etzadroxil/probenecid (oral sulopenem) for the proposed indication of adult patients with uncomplicated urinary tract infection (uUTI) caused by designated susceptible bacteria.

During the discussion, the Committee discussed “a) antimicrobial stewardship issues raised by potential approval and subsequent use of what would be the first oral penem in the US; and b) the most appropriate target patient population(s) for treatment of uUTI with sulopenem etzadroxil/probenecid.”

 Dr. A. Lenore Ackerman on antibiotic stewardship in managing UTIs

A. Lenore Ackerman, MD, PhD, discusses the problem of antimicrobial resistance 

Dr. A. Lenore Ackerman on antibiotic stewardship in managing UTIs

While the committee did not vote on the application, the discussion is anticipated to influence the final FDA decision on the company’s NDA, which has a target action date of October 25, 2024.

Overall, the committee determined that, if approved, oral sulopenem would provide substantial benefit to a subset of patients; there is a risk for off-label use as well as a risk to the community and individuals in the spread of antimicrobial resistance; a plan regarding post-marketing analysis is essential; and observation of changes to the rates of antimicrobial resistance may be necessary.

Below is a live report of the FDA Advisory Committee meeting as covered by 

Following a presentation of all the data, the following 2 questions were posed to the Antimicrobial Drugs Advisory Committee for discussion.

Is the overall benefit-risk assessment favorable for the use of sulopenem etzadroxil/probenecid for this indication?

Considering the totality of the evidence in this application, what are the considerations that would be important to convey to medical providers to ensure appropriate use of sulopenem etzadroxil/probenecid?

On the first point, the proposed indication was again stated as adult women 18 years of age or older who have uncomplicated urinary tract infection caused by designated susceptible microorganisms. Dr. John Farley, director of the Office of Infectious Diseases, FDA, noted that the next step in the application process for oral sulopenem is labeling negotiation between Iterum and the FDA. Farley asked that any opinions regarding wording for the proposed indication be shared.

A definition for “designated susceptible microorganisms” was first discussed. A committee member indicated that their interpretation of the phase was microorganisms susceptible to the proposed agent. If this is the true definition, they suggested they would not support a favorable risk/benefit assessment.

They noted, “In my mind, a positive risk/benefit ratio would require wording that restricts the use to a population at substantially higher risk of treatment failure with currently available first-line oral agents.”

Ideally, they added that this would include patients who had a culture demonstrating resistance to accepted first-line agents. They also brought up the idea of identifying a population of women who are at very high risk for treatment failure with first-line agents, which may be based on demographic features or prior microbiologic results.

A member agreed that the wording was too broad. They also noted that an oral agent may be tremendously beneficial to a subset of patients, but the question remains on how to minimize the risk to society as a whole. The ideal audience, another member reiterated, would be patients with a resistant organism and/or someone who has failed a first-line therapy.

Another question was then posed: Should antimicrobial testing be a requirement? One suggestion was to change the wording of the indication to reflect patients with microorganisms that are resistant to other oral agents. However, it was noted that this still could allow off-label use of the drug. The idea of a requiring a culture also brought up a concern for equity, as some patients may have insurance that doesn’t cover obtaining a culture.

The panel then moved on to the second question regarding considerations for appropriate use.

A committee member questioned about the options available to the FDA if the drug is approved and is then shown, in a post-market setting, to be inappropriately used or to be driving resistance. The agency responded by saying that in the first scenario, the FDA could fall back on labeling, in collaboration with the sponsor, to make changes in the wording of the indication. In the second scenario, there would be more options available to the FDA given that this is considered a safety concern of the drug.

Another committee member suggested that there is also a risk to the individual due to the drug potentially changing their flora, or contributing to "microbiome injury". This, another member added, should be assessed in antimicrobial trials moving forward.

On the issue of labeling, some proposed solutions were to invoke a limitations of use statement indicating this drug for patients with a resistant organism and/or someone who has failed a first-line therapy as well as a possible warning regarding the risk in off-label use of the drug. These actions, in combination with post-marketing assessments of its use in clinical practice as well as assessments of changes to rates of antimicrobial resistance, may support a more favorable risk/benefit ratio for oral solupenem, one panel member concluded.  

Upon returning from break, Angela Kopack, MD, and Xianbin Li, PhD, the clinical and statistical reviewers for the application, presented efficacy and safety assessments on behalf of the FDA.

Li recapped findings from trials 301 and 310 of oral sulopenem, specifically highlighting the difference in the applicant's and FDA's assessments of overall response in the micro-MITTR population in trial 301 due to the applicant’s exclusion of data from site 202. Iterum chose not to include these data on the basis of not being able to validate the findings; the FDA disagreed with the exclusion. As a result, the difference in overall response was 26.6% (

 < .001) in Iterum’s assessment, which decreased to 15.3% (

Kopack agreed on the demonstration of an adequate safety database for oral sulopenem.

Overall, they concluded that trials 301 and 310 provide evidence of benefit with oral sulopenem in proposed indication, and reiterated that the efficacy of oral sulopenem as a stepdown therapy following IV therapy for cUTI has not been established. If approved for uUTI, they note that it will be important to communicate to prescribers the lack of efficacy as a stepdown therapy for cUTI.

In the assessment of clinical pharmacology, which was presented by Henrietta Abodakpi, PharmD, PhD, she noted that oral sulopenem is expected to be safe in patients with mild, moderate, or severe renal impairment, but it is not recommended in patients with creatinine clearance less than 15 mL/min and patients on hemodialysis due to a lack of safety and pharmacokinetic data in these patients.

The discussion was then opened back up to panel members to ask questions. One panel member asked whether the induction of resistance to penems confer resistance to carbapenems. Jalal Sheikh, PhD, the clinical microbiology reviewer for the FDA, responded by saying that cross-resistance is expected.

A committee member then asked for further clarification on why a demonstration of non-inferiority was sought for patients in the micro-MITTS population, given that there isn’t an outstanding unmet need in this group. The FDA responded by saying that at the time of providing the guidance, it appeared that the applicant was seeking to develop oral sulopenem as a first-line treatment option for these patients. From a clinical design standpoint, the advice was provided as an acknowledgement that the pathogen that the patient has needs to be susceptible to the comparator.

The meeting was opened up for panel members to ask questions to the representatives from Iterum Therapeutics.

A concern was raised regarding the design of study 301 given that the trial had hypothesis testing in 2 discordant populations, which a panel member argued is “inferentially identical to doing 2 separate studies”. The investigators did not report alpha sharing to control for type 1 error for this reason. Instead, the panel member pointed out, type 1 error could be reported for each hypothesis.

Another panel member then asked about whether diminished vs preserved renal function or weight impacted response rates. According to Dunne, the response based on creatinine clearance of less than 60 mL/min vs 60 mL/min or more was shown to be comparable in patients who received sulopenem. Thus, adjusting the dose based on renal function is not yet supported. Impact based on body mass index was not fully reported, but data could easily be stratified during the break, Iterum assured.

Another concern was then brought up regarding the potential for AMR occurring in a space that was not assessed. The panel member argued that prior fluroquinolone exposure may predispose them or assessment on intestinal flora could be explored.

A committee member then articulated that one concern is that the introduction of this drug will have a huge impact in the community, and we will lose the benefit a life-saving class, the carbopenems, for “more important infections." Marjorie Golden, MD, FACP, AAHIVS, a paid consultant for Iterum and the site chief of infectious disease at Yale New Haven Hospital, responded by saying that she doesn’t foresee oral sulopenem being the first go-to drug for patients given the impact of prior authorization. On this, she opined that approval of this drug would not “open the floodgates” for broad accessibility of the drug. Further, she argued that for patients who have resistant isolates and no other options, they are receiving a carbopenem now. Approval of oral sulopenem would allow for a different drug with a different route of administration.

A committee member then asked for further clarification regarding the intended population, noting that the overwhelming majority of patients would be those who never had a culture in the first place. Golden said that as a clinician, those who she would see as candidates would be those who have a long history of UTI (and thus a rich microbiologic history). Again, she emphasized that she believes this drug will be one that requires prior authorization in order to get prescribed.

Michael Dunne, MD, FIDSA, a consultant for Iterum Therapeutics, revisited the key questions posed to the advisory committee, which include:

According to Dunne, the previously highlighted data support the safety and effectiveness of oral sulopenem in patients with uUTI. On the second point, Dunne acknowledged that guidance to the prescriber at the time the choice of antibiotic is made could enable appropriate use of sulopenem. Optimally, he adds, there would be a diagnostic test that could alert the physician to patients who may have an organism resistant to existing therapies. Such tools, however, do not yet exist.

To combat this lack of technology, the team at Iterum tried to determine the existence of a variable that might be associated with benefit to sulopenem. The team noted that patients with quinolone susceptible and resistant isolates tended to be older, which is generally supported by existing data in the literature as well as data from trials 301 and 310. Further, the team found that patients over the age of 65 demonstrated a greater response to treatment with sulopenem compared with those treated with comparators (57.7% vs 47.2%).

Dunne stated, “When integrated into care pathways for treatment of uncomplicated UTI, sulopenem could become an important treatment option.”

Dunne also confirmed that Iterum could not support off-label use of oral sulopenem in patients with cUTI with the currently available data, a concern which was raised by the FDA. The proposed indication for oral sulopenem is for adult women with uUTI caused by designated susceptible microorganisms.

Few new antibiotics have been developed over the last 3 decades for patients with uUTI, and there have been rising rates of AMR to all of the approved antibiotics, explained Michael Dunne, MD, FIDSA, a consultant for Iterum Therapeutics in the company’s remarks.

If approved, Dunne noted, “Sulopenem will address an unmet medical need for a reliable, effective treatment of uncomplicated urinary tract infection. Existing antibiotics do not provide confidence in coverage in treatment of uncomplicated UTI because resistance rates are now approaching and may exceed 20% for standard of care options, which challenges the use of empiric therapy for this infection.”

Marjorie Golden, MD, FACP, AAHIVS, a paid consultant for Iterum and the site chief of infectious disease at Yale New Haven Hospital, expanded on the unmet medical need that oral sulopenem will address. According to Golden, UTIs are the most common outpatient infection in women.

Golden noted, “The choice of empiric antibiotics for patients with uncomplicated UTI is often challenging for practicing clinicians and is based on IDSA guidelines as well as a thoughtful assessment of the patient’s overall state, underlying medical conditions, and history of resistant pathogens.”

Golden concluded by re-emphasizing the point that standard of care antibiotics once viewed as viable treatment options for patients with uUTI are becoming increasingly less effective, resulting in delayed cure, need for multiple antibiotic courses, and risk of more serious adverse outcomes. There is a need for new, safe and effective treatment options.

The presentation was then turned back over to Dunne to explain the efficacy, microbiology, and pharmacology of oral sulopenem. He explained that sulopenem has broad activity against the most common organisms in uUTI according to surveillance data collected by the JMI labs from 2016 to 2017. Additional data demonstrate that the activity of sulopenem is consistent with other available penems. Further, oral sulopenem was not found to be associated with clinically relevant drug-drug interactions.

Dunne then walked through the efficacy data supporting the NDA for oral sulopenem.

Study 301 was a multicenter, double-blind, active-controlled study that enrolled 1671 adult women with uUTI. The trial was conducted under the special protocal agreement with the FDA. Patients in the study were randomly assigned 1:1 to receive 500 mg oral sulopenem twice daily for 5 days or 250 mg ciprofloxacin twice daily for 3 days, with matching placebos for each regimen.

The primary end point was the proportion of patients with an overall response rate (clinical success plus microbiologic eradication), as measured at the test of cure visit on day 12. This was measured in 2 analyses: a superiority analysis of oral sulopenem vs ciprofloxacin in patients with uropathogen non-susceptible to ciprofloxacin (micro-MITTR) and a non-inferiority analysis of oral sulopenem vs ciprofloxacin in patients with uropathogen susceptible to ciprofloxacin (micro-MITTS). If the endpoint was reached in any population, a non-inferiority analysis was to be conducted in the broader micro-MITT population.

In the micro-MITTR population, baseline demographics were similar between patients who received oral sulopenem (n = 147) and patients who received ciprofloxacin (n = 139). The overall success rate in the oral sulopenem arm was 62.6% vs 36.0% among patients in the ciprofloxacin arm (difference, 26.6%; 95% CI, 15.1-37.4; 

 < .001). The FDA analysis of this endpoint demonstrated that overall success was achieved in 48.1% of patients in the oral sulopenem (n = 162) arm and 32.9% of patients in the ciprofloxacin (n = 149) arm (difference, 15.3%; 95% CI, 4.3-25.8;

 = .0062). The difference in the total number of patients included in each arm is due to Iterum’s exclusion of patients from 1 particular site due to an inability to validate the data. The FDA analysis also only uses genus and species of the baseline pathogen relative to the organism identified at the test of cure visit. The superiority of oral sulopenem remains the same with either approach.

The superiority of oral sulopenem was also consistent over time, with favorable overall success on day 5, day 12, and on day 28. Additionally, oral sulopenem demonstrated improved response against target uropathogens, namely 

 (100% vs 50%). Superiority was also observed among patients with pathogens non-susceptible to multiple classes of antibiotics.

Based on superiority being established in the non-susceptible population, the analysis of results was triggered in the micro-MITT population, which includes patients with both ciprofloxacin susceptible and ciprofloxacin non-susceptible pathogens. At day 12, the overall success rate was 65.6% in the oral sulopenem arm and 67.9% in the ciprofloxacin arm (difference, -2.3%; 95% CI, -7.9-3.3), demonstrating the non-inferiority of oral sulopenem to ciprofloxacin in the broader population of patients regardless of susceptibly to ciprofloxacin. The clinical success rate was 81.6% and 78.7%, respectively.

In the micro-MITTS population, non-inferiority of oral sulopenem to ciprofloxacin was not achieved, primarily due to microbiologic failure. Overall response in the oral sulopenem arm was 66.8% vs 78.6% in the ciprofloxacin arm (difference, -11.8%; 95% CI, -18.0 to -5.6). Clinical success was achieved in 81.1% of patients in the oral sulopenem arm vs 84.1% in the amoxicillin/clavulanate arm.

Asymptomatic bacteriuria was not shown to impact clinical success at day 28.

Dunne then shifted to data from study 310. Study 310 was a multicenter, double-blind, active-controlled study that enrolled 2222 adult women with uUTI. Patients were randomly assigned 1:1 to receive 500 mg oral sulopenem twice daily for 5 days or 875 mg amoxicillin/125 mg clavulanate twice daily for 5 days with matching placebos for each regimen.

The primary end point was the proportion of patients achieving an overall response of success (clinical success plus microbiologic eradication), as measured at the test of cure visit at day 12.

The first step in this trial evaluated the noninferiority of oral sulopenem to amoxicillin/clavulanate in patients in the micro-MITT population at large. If non-inferiority was achieved, non-inferiority would be measured in the micro-MITTS population and superiority would be assessed in the micro-MITTR population.

In the micro-MITT population, oral sulopenem demonstrated non-inferiority to amoxicillin/clavulanate in overall success at the TOC visit, with an overall success rate of 60.9% vs 55.6%, respectively (difference, 5.4%; 95% CI, -0.8-11.5). Broken down, the clinical success rate was 76.1% in the sulopenem arm vs 76.5% in the amoxicillin/clavulanate arm (difference, -0.4%; 95% CI, -5.7-4.9). The microbiologic success rate was 74.7% in the sulopenem arm vs 67.3% in the amoxicillin/clavulanate arm (difference,7.4%; 95% CI, 1.8-13.1).

Consistent with results from study 301, asymptomatic bacteriuria at day 5 and at day 12 did not predict for clinical failure at day 12 or day 28.

In the micro-MITTS population, the overall success rate with oral sulopenem was 61.7% vs 55% in patients in the amoxicillin/clavulanate arm (difference, 6.7%; 95% CI, 0.3-13.0). In the micro-MITTR population, overall success was achieved in 52.4% of patients in the sulopenem arm vs 68% in the amoxicillin/clavulanate arm. Clinical success was achieved in 77.3% of patients in the oral sulopenem arm vs 76.7% in the amoxicillin/clavulanate arm. However, the study was not sufficiently powered to draw conclusions based on treatment effect due to the small sample size.

Steven I. Aronin, MD, FACP, FIDSA, the senior vice president and head of clinical development for Iterum, was then called to walk through the safety data on oral sulopenem.

In total, 2970 patients and 2964 patients have been treated with oral sulopenem and oral/IV comparators across all phase 3 studies, respectively. This includes 1940 patients with uUTI who were treated with oral sulopenem and 1934 patients with uUTi who were treated with comparators.

Overall, the safety profile for oral sulopenem was consistent across all phase 3 studies. No new safety signals were identified beyond those already known to be associated with b-lactams.

Across trials 301 and 310, which both included patients with uUTI, 21.6% of patients in the oral sulopenem arms experienced any adverse event, compared with 13.0% of patients in the comparator arms. One patient in the oral sulopenem arm died; the death was not considered related to the study drug.

The most common AEs in the oral sulopenem arm were diarrhea (8.9%), nausea (4.1%), headache (2.2%), vomiting (1.5%), loose stools (1.3%), and vulvovaginal mycotic infection (1.0%).

One patient in study 302, assessing oral sulopenem in patients with cUTI, met the criteria for Hy’s law. This patient was a 75 year old man with cUTI without pyelonephritis whose concomitant medications included 300 mg of valproic acid twice daily. According to Aronin, the label for oral sulopenem, if approved, would include a warning about concomitant use of valproic acid, in line with other penems.

Peter Kim, MD, MS, director of the division of anti-infectives (DAI) in the office of infectious diseases (OID) at the FDA’s Center for Drug Evaluation and Research (CDER), delivered the agency’s opening remarks earlier this morning.

Kim acknowledged that there are multiple FDA approved oral antibacterial drugs. However, he explained that current treatment options can be limited by adverse reactions and antimicrobial resistance (AMR).

Kim noted, “While an oral penem could potentially address an unmet need for the treatment of uUTI caused by resistant bacteria, its use in an ambulatory setting where treatment is most commonly empiric raises concerns for inappropriate use, which may contribute to AMR.”

In reviewing the clinical program supporting the NDA for oral sulopenem, Kim highlighted variable efficacy findings from several phase 3 trials of the drug. In uUTI Trial 201, the efficacy of oral sulopenem was established in the ciprofloxacin-resistant population, but not in the ciprofloxacin-susceptible population, which was primarily due to microbiologic failure. Microbiologic failure was defined as post-treatment microbiologic persistence. Similarly, in uUTI Trial 310, the efficacy of oral sulopenem was established in the amoxicillin/clavulanate-susceptible population, with inconclusive results in the amoxicillin/clavulanate-resistant population due to small sample size.

Two additional phase 3 trials were conducted for oral sulopenem in patients with complicated UTI (cUTI) and complicated intra-abdominal infections (cIAI). Trial 302 enrolled patients with cUTI, demonstrating that IV to oral sulopenem was noninferior to a comparator IV to oral regimen in overall response, which was measured as a composite of both clinical and microbiologic response. Additionally, Trial 303 enrolled patients with cIAI, finding again that IV to oral sulopenem did not demonstrate a noninferior overall response rate vs a comparator IV to oral regimen.

Kim also highlighted the adequate safety data supporting oral sulopenem. He noted that the identified safety risks could potentially be mitigated through labeling. Diarrhea was the most common adverse event (AE) in patients with uUTI but was generally mild and did not lead to any treatment discontinuations. Additionally, a small proportion of patients treated with oral sulopenem experienced mild alanine aminotransferase (ALT) elevations that were not treatment-limiting.

Kim brought forward several considerations in the potential approval of oral sulopenem for this patient population. To start, the 2 phase 3 trials in patients with uUTI were conducted in an ambulatory setting and were not designed to evaluate the efficacy of oral sulopenem for the treatment of uUTI caused by resistant bacterial isolates or for the treatment of uUTI in patients who failed first-line therapy.

Further, there is concern that oral sulopenem may be used off-label for the treatment of cUTI or other infections as stepdown treatment in the context of noninferiority findings with IV sulopenem followed by oral sulopenem to the active comparator regimen in trial 302. Kim noted that currently, there are no data on the effectiveness of oral sulopenem as stepdown therapy following IV treatment of cUTI with another antibacterial drug.

Additionally, if approved, oral sulopenem would mark the first oral penem approved in the US. Inappropriate use of this drug may contribute to AMR or increase cross-resistance to other penem drugs.

Kim concluded in his remarks, “While antimicrobial stewardship and consideration by guidelines committees may help to determine the appropriate positioning of oral sulopenem, if approved, in the hierarchy of uUTI treatment, a discussion of approaches to inform prescribers of relevant data submitted in this NDA to ensure the most appropriate use of oral sulopenem is warranted.”

Iterum Therapeutics initially submitted their NDA for oral sulopenem in January 2021.

 The FDA issued a complete response letter in July 2021, requesting additional data in order to support approval on oral sulopenem for the treatment of adult women with uUTI.

Following their guidance, Iterum entered into a special protocol assessment agreement with the FDA to conduct a phase 3 trial that would adequately address the objectives necessary to support potential resubmission of their NDA.

 Thus, the phase 3 REASSURE (REnewed ASsessment of Sulopenem in uUTI caused by Resistant Enterobacterales) trial was conducted to compare oral sulopenem with oral amoxicillin/clavulanate (augmentin) in the treatment of women with uUTI.

Follow Urology Times' coverage of the full-day FDA advisory committee meeting regarding Iterum Therapeutics' new drug application for oral sulopenem for uncomplicated urinary tract infection.

Jim Tudor, PCA, CPC

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