Non-Viral Gene Therapy in BCG-Unresponsive Bladder Cancer: LEGEND Phase 2 Pivotal Cohort Results

KEY FINDINGS

• Trial: LEGEND - an open-label, multi-cohort phase 2 trial. Pivotal Cohort 1: 125 patients with BCG-unresponsive, high-risk disease including CIS (carcinoma in situ). Data cut-off 21 April 2026; the results were presented in a plenary session at AUA 2026.
• Treatment: Detalimogene voraplasmid - an intravesically administered gene therapy containing no viral vector (DDX® oligochitosan carrier platform).
• Complete response: 54% at any time (67/124; 95% CI 45-63%); 91% of responses were achieved at the first disease assessment.
• Complete response at month 6: 43% (52/121; 95% CI 34-52%).
• Durability: Duration of response at 12 months (Kaplan-Meier) 25% (95% CI 11-41%); median duration of response 37.3 weeks.
• Progression: Progression to muscle-invasive or more advanced disease in only 3.2%.
• Safety: Treatment-related adverse events in 55%; 91% of these were grade 1-2. Grade 3 events in 6 patients (4.8%); treatment discontinuation 2.4%.

Background: Why Is BCG-Unresponsive Disease a Critical Threshold?

Approximately 75-80% of newly diagnosed bladder cancers are non-muscle-invasive (NMIBC). In the high-risk subset of this group the standard treatment is intravesical BCG. However, in patients who become unresponsive to BCG, recurrence rates reach 50-70% and the next step regarded as curative is radical cystectomy.

Radical cystectomy is oncologically effective; but because of its permanent effects on urinary diversion, sexual function, body image and quality of life it is a life-transforming intervention for patients. The need for bladder-sparing alternatives is high particularly in patients of advanced age, with comorbidities, or who do not accept surgery.

Carcinoma in situ (CIS) is the most challenging component of this need, because it progresses as flat, multifocal lesions in the bladder wall that cannot be resected. In recent years nadofaragene firadenovec, nogapendekin alfa inbakicept and oncolytic adenovirus-based approaches have aimed to fill this gap.

Detalimogene voraplasmid - mechanism of action: A non-viral gene therapy produced with the DDX® (Dually Derivatized Oligochitosan) platform developed by enGene. When instilled into the bladder it penetrates the mucosal tissue and is intended to trigger a localised - not systemic - antitumour immune response. Its independence from viral vectors carries the potential for practical advantages in terms of cold chain, safe handling and manufacturing processes. The agent has received RMAT and Fast Track designations from the FDA.

Study Design

LEGEND is an ongoing, open-label, multi-cohort phase 2 trial evaluating the safety and efficacy of detalimogene in high-risk NMIBC. Cohort 1, intended to form the basis of the planned Biologics License Application (BLA), consists of 125 patients with BCG-unresponsive disease including CIS.

Key Results

91% of responses were achieved at the first disease assessment; this shows that the effect of the treatment emerges early. Of the patients given re-induction, 14% (6/43) converted from a non-complete-response state to a complete response. Of the 52 patients in response at month 6, 37 of the 44 who completed the month 9 assessment and 13 of the 22 who completed the month 12 assessment remained in complete response; a further 21 patients still have the potential to achieve a complete response at month 12 - the durability data must therefore be regarded as immature.

Safety

At least one treatment-related adverse event was observed in 69 of the 125 patients assessed (55%).

Grade 3 adverse events were reported in six patients, one of whom had a grade 4 event, which resolved. No grade 5 (fatal) treatment-related adverse event was reported. Rates of dose discontinuation (2.4%) and dose interruption (2.4%) were low.

Note: In the 32 patients undergoing their first disease assessment after the previous data cut-off (24 October 2025), complete response rates were lower: 39% at any time and 32% at month 6. A preliminary subgroup analysis revealed no significant difference in demographic or baseline disease characteristics, and a comprehensive analysis is ongoing. This heterogeneity calls for caution in interpreting the results.

Implications for Clinical Practice

1. The efficacy-durability balance in bladder-sparing treatment

The LEGEND data show clearly that in bladder-sparing approaches the early complete response rate is not a sufficient measure on its own. A 54% initial complete response rate set against a 25% durability of response at 12 months makes realistic expectation management essential in patient selection and counselling.

2. The low risk of progression is a strategic advantage

The 3.2% rate of progression to muscle-invasive disease is one of the most meaningful findings for this treatment. The great majority of patients who lose response can be directed to radical cystectomy or alternative bladder-sparing treatments without having lost the chance of cure - but only with a rigorous cystoscopic surveillance protocol.

3. The tolerability profile supports ambulatory administration

That the great majority of adverse events were grade 1-2 and that the discontinuation rate remained at 2.4% supports the feasibility of administering the agent in the outpatient setting.

4. The logistical potential of a non-viral platform

A manufacturing and administration model requiring no viral vector promises operational ease compared with existing gene therapies in terms of cold chain, biosafety level and preparation processes.

5. The regulatory process and timing

For detalimogene, which has RMAT and Fast Track designations and is included in the CDRP programme, manufacturing validation batches have been completed and the Statistical Analysis Plan has been submitted to the FDA. The approval scenario will be shaped by the maturation of the durability data.

Conclusion

The LEGEND pivotal cohort establishes that non-viral intravesical gene therapy in BCG-unresponsive high-risk NMIBC is a feasible, well-tolerated and clinically active approach. A complete response of 54% at any time and 43% at month 6 is an indicator of meaningful activity in this population with limited options.

Nevertheless, the 25% durability of response at 12 months is the variable that will determine the agent's place in the sequence of bladder-sparing treatments. At this stage detalimogene can be positioned less as a curative solution in itself than as a "bladder preservation window" that, thanks to its low progression risk, does not close off the patient's subsequent treatment options.

The field must be assessed as a whole: together with nadofaragene firadenovec, cretostimogene grenadenorepvec (BOND-003), gemcitabine-releasing systems and UGN-102-based chemoablation approaches, the management of NMIBC is rapidly turning into a field with many options and open to biomarker guidance. Which patient should receive which agent, and in what order, is the fundamental clinical question of the period ahead.

References

• enGene Therapeutics Inc. enGene Announces Updated Interim Results From LEGEND Pivotal Cohort. 7 May 2026.
• OncLive. Detalimogene Voraplasmid Yields 54% CR Rate in Heavily Pretreated BCG-Unresponsive NMIBC With CIS.
• UroToday. Interim Phase 2 LEGEND Trial Results for Detalimogene in BCG-Unresponsive NMIBC - Ashish Kamat.
• Urology Times. Pivotal cohort in LEGEND trial reaches target enrollment.
• Renal & Urology News. Non-Viral Gene Therapy Shows Promise for BCG-Unresponsive NMIBC With CIS.