FDA Grants RMAT Designation for Detalimogene in NMIBC
Detalimogene voraplasmid gains FDA RMAT designation, showcasing a 71% response rate in treating high-risk, BCG-unresponsive NMIBC with promising safety.
US FDA
- Detalimogene voraplasmid (detalimogene; previously EG-70) has received regenerative medicine advanced therapy (RMAT) designation from the FDA for high-risk, Bacillus Calmette Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), indicating promising early clinical results and an expedited regulatory pathway.
- Preliminary data from the ongoing pivotal phase 2 LEGEND trial (NCT04752722) show a compelling 71% overall complete response (CR) rate in BCG-unresponsive NMIBC with CIS, alongside a favorable safety profile.
- Detalimogene is a novel, nonviral, gene-based immunotherapy designed for intravesical administration, aiming to stimulate a local antitumor immune response and provide a bladder-preserving option for patients with limited alternatives.
The FDA has granted RMAT designation to detalimogene voraplasmid for the treatment of patients with high-risk, BCG-unresponsive NMIBC with CIS.1 This designation underscores the therapy's potential to address a significant unmet medical need in a patient population facing limited treatment options, often including radical cystectomy.
The RMAT designation is based on preliminary results from the ongoing pivotal phase 2 LEGEND trial, which has demonstrated compelling clinical activity and a generally favorable tolerability profile. The LEGEND study is an open-label, multicohort trial evaluating the safety and efficacy of intravesical detalimogene in high-risk NMIBC. The pivotal cohort 1 of the study, enrolling approximately 100 patients with high-risk, BCG-unresponsive NMIBC with CIS (with or without papillary disease), is intended to support a biologics license application filing.
Preliminary data from this cohort have shown an impressive overall CR rate of 71% (15/21 evaluable patients), with CR rates of 67% at 3 months and 47% at 6 months.
Artistic rendering of bladder cancer
Beyond the pivotal cohort 1, the LEGEND trial includes additional cohorts: cohort 2a for BCG-naive patients with NMIBC with CIS, cohort 2b for patients with NMIBC with CIS who have received inadequate BCG treatment, and cohort 3 for patients with BCG-unresponsive high-risk NMIBC with papillary-only disease. The trial is actively enrolling patients across sites in the USA, Canada, Europe, and the Asia-Pacific region.
“Receiving the RMAT designation highlights the promising profile of detalimogene and its potential to address the high unmet need in NMIBC,” said Ron Cooper, chief executive officer of enGene, in a press release. “Bladder cancer patients with limited options cannot wait, and we are enthusiastic about potentially expediting the regulatory process to bring a first-in-class treatment to patients.”
About Detalimogene Voraplasmid
Detalimogene is a novel, investigational, nonviral gene-based immunotherapy designed for streamlined administration in urology clinics. Its mechanism of action involves the nonviral stimulation of a local immune response within the bladder. This is achieved by delivering genetically encoded immunostimulatory payloads, specifically interleukin-12 and agonists of RIG-I, via the company’s Dually Derivatized Oligochitosan platform.
Preclinical data indicate that detalimogene promotes a shift in the tumor microenvironment from an immunosuppressive to a proinflammatory state, leading to immune cell recruitment, tumor clearance, and durable, memory-mediated protection against tumor rechallenge. This localized immune activation aims to provide a powerful antitumor effect while mitigating systemic toxicities often associated with other immunotherapies.
The RMAT designation is intended to expedite the development and review of regenerative medicine therapies for serious or life-threatening conditions where preliminary clinical evidence suggests the potential to address unmet medical needs. This designation provides several regulatory advantages, including enhanced and more frequent engagement with the FDA, potential for rolling review, and eligibility for priority review.
In addition, detalimogene had previously received fast track designation from the FDA, further highlighting its potential to address the high unmet medical need in BCG-unresponsive CIS NMIBC, particularly for patients who are not candidates for or decline cystectomy.
Methods/Design of the LEGEND Trial
For phase 2 of the LEGEND trial, patients must be aged 18 years or older with an ECOG performance status of 0, 1, or 2, and satisfactory bladder function with the ability to retain the study drug for at least 60 minutes. Patients who have previously failed treatment with a checkpoint inhibitor are eligible for inclusion, with specific washout periods (30 days posttreatment for phase 1, 3 months posttreatment for phase 2). Patients must also have adequate bone marrow, renal, and hepatic function, a prothrombin time and partial thromboplastin time ≤1.25 x ULN or within therapeutic range if on anticoagulation, and for patients with T1 lesions in phase 2, eligibility may require a repeat transurethral resection of bladder tumor to show noninvasive (Ta or less) or no residual disease.2
Women of childbearing potential must have a negative pregnancy test at screening and agree to use highly effective birth control methods. Male patients must use a condom for the duration of study treatment and for 3 months postdose.
The primary end points for the phase 2 portion of the LEGEND trial are the percentage of patients with cystoscopic CR at 48 weeks, based on examination, urine cytology, and appropriate biopsies; and the nature, incidence, relatedness, and severity of treatment-emergent adverse events. Secondary end points include progression-free survival, CR rates at various time points (12, 24, 36, and 96 weeks), duration of response, and quality of life assessments.
The safety profile observed thus far has been favorable, with treatment-related adverse events being predominantly grade 1/2 in severity, with common events including dysuria, bladder spasm, pollakiuria, and fatigue.1
The ongoing LEGEND trial will continue to provide critical data to support the therapy's efficacy and safety for this challenging oncological condition.
