FDA Advisory Committee finds evidence for UGN-102 inconclusive, cites uncertainty in benefit-risk

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 4-5 in opposition of a favorable benefit-risk profile for UGN-102 (mitomycin) intravesical solution in adult patients with recurrent low-grade intermediate-risk non–muscle invasive bladder cancer (LG-IR-NMIBC).¹

The PDUFA target action date for UGN-102 is June 13, 2025.

The ODAC meeting was called to discuss the submitted new drug application (NDA) for UGN-102, which the agency previously accepted in October 2024, issuing a Prescription Drug User Fee Act (PDUFA) target action date of June 13, 2025.²

The recommended dose level for UGN-102 is 75 mg (56 mL) instilled once weekly for 6 weeks. Approval of UGN-102 would mark the first FDA-approved treatment for LG-IR-NMIBC.

During the meeting, the ODAC discussed whether:

• “Durable complete response assessed in a single-arm trial can establish efficacy in the LG-IR-NMIBC population.
• The overall benefit-risk of the investigational treatment is favorable.”

On the second point, 4 committee members voted “yes”, and 5 committee members voted “no”.

Although the FDA relies on the ODAC meeting to inform their pending regulatory decisions, the agency is not bound by the consensus that the group reaches.

Please find updates from the ODAC meeting below, which were recorded live by the Urology Times® editorial team.

11am update:

Following sessions on clarifying questions and public commentary, the meeting entered into a discussion of the 2 questions posed to the committee.

The committee began by reflecting on the question, “Given uncertainty regarding interpretation of duration of response in low-grade intermediate-risk non–muscle invasive bladder cancer (LG-IR-NMIBC), should randomized trials should be required in the future to assess the effectiveness of therapies in this disease setting?”

In general, the committee appeared in agreement about the benefit of randomized controlled trials, noting that they are the preferable option. However, many committee members expressed concerns over the word “required,” instead saying that the decision to proceed with an RCT should be done based on the individual therapy. The FDA then noted that if not required, RCTs may not be conducted at all.

The committee then proceeded to question 2, which the ODAC voted on. The question is as follows: Is the overall benefit-risk of the investigational therapy UGN-102 favorable in patients with recurrent LG-IR-NMIBC?

Overall, 4 committee members voted “yes”, and 5 committee members voted “no”.

Those who voted “no” largely argued that there were too many uncertainties given a lack of a control arm in the ENVISION trial. Panel members explained that the benefit of UGN-102 was difficult to ascertain for this reason. Likewise, while the low-grade toxicity was promising, the overall risk was difficult to quantify. Panel members argued that randomized controlled trials in this setting appear to be feasible, and this was a missed opportunity to generate that data.

Those who voted “yes” acknowledged that a randomized controlled trial would have served better in this setting, but still maintained that the efficacy data was compelling and the safety data were not concerning. They also argued that delaying the time to surgery, as many patients pointed out during the public hearing, is an immense benefit.

9:30am update:

Brian Heiss, MD, clinical reviewer, genitourinary malignancies for the FDA, was called to summarize what had been previously discussed.

He reminded the committee of the discussion question: Given uncertainty regarding interpretation of duration of response in LG-IR-NMIBC, discuss whether randomized trials should be required in the future to assess the effectiveness of therapies in this disease setting.

He also reiterated the voting question: Is the overall benefit-risk of UGN-102 favorable in patients with recurrent LG-IR-NMIBC?

Heiss then recapped previous efficacy and safety data from both ATLAS and ENVISION.

He also shared data from an FDA-conducted exploratory analysis, which matched the inclusion criteria of ATLAS to that of the ENVISION trial. This meant excluding patients who were newly diagnosed from the ATLAS study. This yielded 51 patients who received UGN-102 and 57 patients who received TURBT.

Per this analysis, data showed a 3-month CR rate of 72.5% (95% CI, 58.3% to 84.1%). This is consistent with data from ENVISION.

However, in the post-hoc analysis, 40.5% (95% CI, 24.8% to 57.9%) of patients remained in CR at 12 months, which is considerably lower than that seen in ENVISION (79.2%). Heiss stressed again that this was an exploratory analysis only.

Heiss also noted that it is hard to determine if UGN-102 would result in a reduction in future TURBTs, or if it would only prevent the initial TURBT that is being replaced by the medical therapy.

9:15am update:

Sunil Raju, MBBS, BSc, vice president of clinical development for UroGen Pharma, detailed the safety profile for UGN-102. Among the 449 patients enrolled across all studies of UGN-102, 94.2% of patients received all 6 instillations of treatment.

Any occurence of a treatment-emergent adverse event (TEAEs) was reported in 68.2% of patients. Treatment- and procedure-related AEs were 39.2% and 29.2%, respectively. In total, 4.2% of patients discontinued treatment due to TEAEs. The majority of TEAEs occurred in the first 3 months of treatment.

The most common AEs were dysuria (27.6%), pollakiuria (11.6%), and micturition urgency (9.6%). The median time to onset of lower urinary tract symptoms was 17 days, the median duration of the first event was 8 days.

There did not appear to be a clinically meaningful risk of bone marrow suppression.

Max Kates, MD of Johns Hopkins Brady Urological Institute in Baltimore, Maryland, was then invited to share his clinical perspective. Kates reported financial disclosures with UroGen, but noted that he has no financial interest in the outcome of this meeting.

He reiterated the idea that UGN-102 can provide an option to help break the cycle of recurrences and repeated TURBTs. In his experience, the efficacy data of UGN-102 demonstrates an effect distinct from the natural history of disease.

He also noted that based on ENVISION data, he would be able to tell patients that they have a 70% chance or avoiding TURBT in the first year and a 63% chance of avoiding TURBT in the first 2 years.

He also noted the convenience of UGN-102 compared to TURBT. UGN-102 is administered in the urology office by a nurse, with no general anesthesia, and generally takes less than an hour in procedural time. Patients can resume to normal activities immediately afterwards. With TURBT, on the other hand, patients need to be treated in the hospital or surgery center, under general anesthesia, and the procedure generally takes around 4 to 6 hours. Patients take 2 to 3 days, sometimes longer, to return to normal activity. These considerations are even more exaggerated with repeated TURBTs, Kates noted.

He also reflected on the patients who he would not consider for UGN-102: those newly diagnosed, those who are healthy with infrequent small recurrences, and those who have disease that can be managed with in-office fulguration or active surveillance.

8:45am update:

Mark Schoenberg, MD, chief medical officer of UroGen Pharma and a practicing urologist, delivered opening remarks on behalf of the company. Schoenberg reiterated the potential value of UGN-102 in providing patients with the only non-surgical option in LG-IR-NMIBC.

The company also has another platform technology and active drug with the same mechanism as UGN-102: Jelmyto. Schoenberg noted that Jelmyto was approved on the basis of a single-arm trial.

In ATLAS, Schoenberg explained that the FDA required a superiority study, whereas ATLAS was designed as a non-inferiority trial. The ATLAS trial was then halted, and ENVISION was initiated.

Schoenberg noted, “If approved, UGN-102 can break the cycle of repeated TURBTs.”

Sam Chang, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, then provided commentary on the potential value of UGN-102 in LG-IR-NMIBC, if approved. Chang is a paid consultant of UroGen but noted that he had no financial interest in the outcome of this meeting. He explained that LG-IR-NMIBC is a highly recurrent disease, with repeated TURBT having a significant burden on patients. Therefore, there is a need for a non-surgical alternative for this patient population.

Michael J. Louie, MD, MPH, MSc, executive vice president of clinical development and medical affairs for UroGen, was then invited to share efficacy data on UGN-102.

ENVISION

In total, the ENVISION trial enrolled 240 patients across 56 sites in 10 countries. To be eligible for enrollment, patients needed to have a history of LG-NMIBC treated with TURBT. Baseline demographics and tumor characteristics in the trial are consistent with the LG-IR-NMIBC population in the US, according to Louie.

Those enrolled in the study received 6 once-weekly instillations of UGN-102 during the study.

The CR rate, as previously mentioned, was 77.6% at 3 months. The CR rate was consistent across study subgroups. CR was also durable, with a median DOR not estimable at a median follow-up at 19.1 months. The DOR was 83.3% (95% CI, 76.7% to 88.1%) at 12 months, and 81.2% (95% CI, 74.4% to 86.4%) at 18 months.

Since patients enrolled had previously underwent TURBT, patients were asked whether they recommended UGN-102 or TURBT in the form of structured interviews. In total, 90% of patients recommended UGN-102 over TURBT. Respondents indicated a preference of UGN-102 due to less impact on work, recreation, exercise, and sexual activity; less bleeding; and shorter-lasting urinary catheter-related issues.

The ENVISION trial is ongoing, with follow-up planned for up to 5 years.

ATLAS

In total, ATLAS enrolled 282 patients who were randomly assigned to receive UGN-102 or TURBT.

At 3 months, the CR rate was 72.5% in the UGN-102 arm vs 56.1% in the TURBT arm. The duration of response was also longer in the UGN-102 arm. The median DOR was not estimable in the UGN-102 arm and was 9.1 months in the TURBT arm.

At 12 months, 65.2% of patients in the UGN-102 arm remained in CR, compared with 41.9% in the TURBT arm.

Data also showed a reduction in TURBTs among those in the UGN-102 arm.

8am update:

The meeting began with Sundeep Agrawal, MD, clinical team lead of genitourinary malignancies at the FDA, providing opening remarks on behalf of the agency.

Agrawal introduced UGN-102 (mitomycin), an intravesical solution in a reverse thermal gel formulation. Mitomycin hydrogel was previously approved to treat low-grade upper tract urothelial carcinoma.

He then reminded the committee of the purpose of the ODAC meeting, which is as follows:

• Given uncertainty regarding interpretation of duration of response in LG-IR-NMIBC, discuss whether randomized trials should be required in the future to assess the effectiveness of therapies in this disease setting.
• Is the overall benefit-risk of UGN-102 favorable for patients with recurrent LG-IR-NMIBC?

According to Agrawal, in patients with Ta and T1 tumors in NMIBC, recurrence risk is 15% to 61% at 1 year and 31% to 78% at 5 years. Similarly, the progression risk in these patients is 1% to 17% at 1 year and 1% to 45% at 5 years. In the trials supporting UGN-102, patients enrolled in the study had Ta disease.

He went on to explain that the natural history of intermediate-risk disease is difficult to predict, with management varied based on individual patient characteristics.

Currently, the standard procedure for these patients is TURBT. However, this treatment option comes with some risk, with 30-day complication rates ranging from 5% to 8%, according to Agrawal. Repeated TURBTs may also increase cumulative risk.

UGN-102 is intended to offer a non-surgical option for patients with LG-IR-NMIBC.

During the regulatory pathway, FDA encouraged UroGen to initiate a randomized trial to assess the efficacy and safety of UGN-102. This was done in the ATLAS trial, where patients were randomly assigned to UGN-102 or TURBT; however disease-free survival was defined differently in both arms, and the FDA did not agree with all aspects of the trial design.

The agency explained that a single-arm trial could sufficiently support approval, but the trial would need to be large and demonstrate treatment affect distinct from the natural history of disease.

ATLAS was then terminated early by the company as a financial decision, in an effort to pursue the single-arm ENVISION trial. The primary end point for ENVISION was complete response rate at 3 months, with DOR as a key secondary end point.

However, Agrawal noted several challenges with single-arm trial designs, such as the potential for selection bias and the lack of a concurrent control arm, which requires a historical control to put the safety and efficacy data in context.

The agency did note, however, that single-arm trials have supported drug approvals in the past.

Agrawal then posed the first discussion point again: Given uncertainty regarding interpretation of duration of response in LG-IR-NMIBC, should randomized trials should be required in the future to assess the effectiveness of therapies in this disease setting?

Based on data from ENVISION, Agrawal maintained that UGN-102 has activity and may offer a non-surgical option in LG-IR-NMIBC. However, without a control arm, it is difficult to determine if the DOR is due to efficacy of the drug, or instead to the natural history of disease. It is also difficult to interpret the safety of UGN-102 compared to other options, such as TURBT.

Background

The NDA for UGN-102 is primarily supported by findings from the phase 3 ENVISION trial (NCT05243550), which met its primary end point by demonstrating a 79.6% (95% CI, 73.9% to 84.5%) complete response rate in patients with LG-IR-NMIBC at 3 months following the first instillation of the therapy.

Updated data from the trial, which were reported in June 2024,³ showed that the 12-month duration of response (DOR) was 82.3% (95% CI, 75.9% to 87.1%) per Kaplan-Meier estimate among those patients who achieved a complete response at 3 months following the first instillation (n = 108) of UGN-102. The study also reported a DOR of 80.9% (95% CI, 73.9% to 86.2%) at both 15 (n = 43) and 18 (n = 9) months, per Kaplan-Meier estimates.

During the ODAC meeting, the FDA is specifically seeking guidance on whether the observed DOR can be attributed to UGN-102, or if it reflects the natural history of the disease. The agency also noted the lack of a control arm in the ENVISION trial, which prevented the generation of comparable safety data to other treatment options in the setting. According to the FDA, this “typically includes transurethral resection of bladder tumor (TURBT) with or without a single post-operative instillation of intravesical chemotherapy.”

In recounting their discussions with UroGen, the agency added, “The FDA further stated that demonstrating treatment effect that is distinct from the natural history of the disease would be critical, safety results would be considered, and the proposed follow-up of 18 months after response may not adequately capture durability. Lastly, the FDA noted to the Applicant that an NDA supported by data generated in a single-arm trial would likely require discussion at ODAC.”

REFERENCES

1. May 20-21, 2025 Meeting of the Oncologic Drugs Advisory Committee. US Food & Drug Administration. Accessed May 21, 2025. https://www.fda.gov/media/186526/download

2. UroGen announces FDA acceptance of its new drug application for UGN-102. News release. UroGen Pharma Ltd. October 15, 2024. Accessed May 21, 2025. https://investors.urogen.com/news-releases/news-release-details/urogen-announces-fda-acceptance-its-new-drug-application-ugn-102

3. UroGen announces unprecedented 82.3% duration of response at 12 months in the ENVISION trial investigating UGN-102 as potentially the first FDA-approved non-surgical treatment for LG-IR-NMIBC. News release. June 13, 2024. Accessed May 21, 2025. https://investors.urogen.com/news-releases/news-release-details/urogen-announces-unprecedented-823-duration-response-12-months