BiQ: Urogen Drops on Release of ADCOM Briefing Documents (URGN)

Urogen (URGN) shares fell by ~25% today after the FDA released the briefing document for the upcoming ADCOM meeting on May 21st. The document can be found here: https://www.fda.gov/media/186526/download (shout out to BiQ members @MarcusCrassus and @Pascal for sharing this link in BiQ chat.)

The fact that there would be an ADCOM meeting was widely known and previously communicated by management. It was also widely known that URGN decided to run a single-arm trial for UGN-102 as opposed to a randomized placebo-controlled trial, which is what necessitated the ADCOM meeting. However, the release of the briefing documents still precipitated the steep pullback in the share price, probably because of the tone that the FDA struck in its comments.

From my perspective, while I didn't see anything new in the briefing docs that wasn't already anticipated, I definitely think the FDA wanted to make their point. The main criticism voiced by the FDA was that the lack of a randomized trial made it difficult to interpret the safety and efficacy of UGN-102. The crux of it can be summarized in the FDA's comments here:

The FDA recommended a randomized trial design to the Applicant several times during their product’s development due to concerns with interpreting efficacy results and distinguishing whether any observed efficacy would be due to the investigational therapy or the natural history of the disease, as well as concerns with lack of comparative safety data against a concurrent control.

While this is a significant risk factor, it isn't new information. The FDA suggested a randomized trial, and Urogen decided to run a single-arm trial instead due to disagreements over trial design. The primary disagreements seemed to center around the selection of endpoints and the definition of DFS. With regards to DFS, here's what the FDA had to say:

The FDA did not agree with the differential definition of DFS between arms, where residual disease at the 3-month assessment in the UGN-102 ± TURBT arm was not considered a DFS event but was considered a DFS event in TURBT arm. The definition of DFS events should be applied consistently across both arms to ensure that the observed treatment effect is attributed to the true differences in the treatment rather than discrepancies in the event definition.

The challenge here was that UGN-102 takes time to have effect, whereas the removal of target lesions via TURBT is immediate. At 3 months, it may have been challenging to distinguish between new and recurrent lesions observed following UGN-102 administration.

Another point of dispute was the selection of endpoints. Urogen wanted to run a non-inferiority trial with DFS as the primary endpoint. Here's what the FDA had to say:

Prior to terminating the trial, ATLAS was designed as a non-inferiority study with the primary endpoint of DFS to be tested hierarchically for non-inferiority followed by superiority. The FDA did not agree with the non-inferiority design with DFS as the primary endpoint. In general, non-inferiority trials with time-to-event endpoints other than overall survival are not appropriate. It is challenging to establish an appropriate non-inferiority margin in this setting. In addition, the handling of NCR patients in the UGN-102 arm may show that two inherently different treatments are similar using DFS.

The FDA also disagreed with Urogen's interpretation of secondary endpoints from Envision:

For the secondary endpoint of DOR, the KM method is generally not used by FDA to estimate the durability of CR at a landmark time point, as the KM assumptions may overestimate the proportion of patients who remained in CR, particularly when follow-up is limited. Instead, the FDA evaluates the observed proportion of patients who remained in CR at the landmark time point, considering only those who were still being followed and confirmed to be in CR at that specific time.

For another secondary endpoint, DCR, the discrepancy between the FDA analysis and Applicant’s reported DCR proportion is mainly due to how follow-up timing was handled. The FDA used the exact timing of events or censoring, while the Applicant grouped data by scheduled visit windows, each spanning a 90-day period. Additionally, the Applicant used imputed data for DCR analysis, though this only affected the results for a small number of patients. However, the imputation approach was generally optimistic.

Patient-reported outcomes (PROs) and qualitive patient preference interviews are challenging to interpret due to the single-arm study design. See Section 4 for discussion of PROs.

I don't know what the alternative would have been, but after reading through the briefing, I think Urogen definitely pursued a risky strategy by running a single-arm trial. The question that ADCOM participants must now answer, as stated by the FDA, is this:

Is the overall benefit-risk of the investigational therapy UGN-102 favorable in patients with recurrent LG-IR-NMIBC?

One point that I think will be hotly debated is how to interpret the UGN-102 data against the natural history data in the absence of a control arm, and it's above my pay grade to try to predict the outcome. However, my personal opinion is that while the totality of the data may not prove that UGN-102 is superior to TURBT, I think it does support a case for non-inferiority.

TURBT is a surgical procedure that must be performed under anesthesia in a hospital or surgery center setting. Furthermore, repeated TURBTs can lead to additional comorbidities such as bladder perforation, increased recurrence rates, bladder scarring, reduced bladder capacity, and complications from the use of anesthesia. In contrast, UGN-102 is non-surgical, doesn't require the use of anesthesia, can be applied in a doctor's office, and has a relatively benign safety profile.

I think there are two potential outcomes to the PDUFA. The first is that UGN-102 could be approved. The second is that the FDA could require Urogen to run an additional, lengthy, randomized trial. In the second scenario, I expect URGN will likely abandon 102 and focus its efforts on advancing 103/104 instead. Still, this makes the outcome of the ADCOM a critical event for Urogen and its investors.

I have no way of predicting what will happen; however, personally, I think the benefits of UGN-102, as a relatively safe and non-surgical alternative to TURBT, outweigh the risks for LG-IR-NMIBC patients. However, given the uncertainty of approval and the FDA's feedback on the ADCOM briefing, I believe any investment in URGN should be approached with a healthy degree of caution.

Please refer to the BiQAP Live spreadsheet on the Active Portfolio page or the iQCS for additional information.

URGN share price at time of publication: $7.31.

Not a BiQ Premium member? Try BiQ Premium for $10 (80% off) for the first month, or $250 (50% off) for the first year.

Biotech iQ is 100% subscriber supported. If you find this information helpful, please spread the word. You can also follow me on X @ Biotech iQ (_Biotech_iQ).

Biotech iQ is not an investment professional, and nothing on this page or this website should be considered investment advice. Please consult with a licensed investment professional as necessary. Past performance is not indicative of future results.