Introduction:

enGene has developed a non-viral gene therapy platform for delivery of nucleic acids to the epithelia of mucosal tissues.  Detalimogene voraplasmid (EG-70), enGene’s lead product, carries a plasmid that simultaneously expresses a recombinant single-chain human interleukin-12 (IL-12) and two double-stranded RNA activators of the intracellular innate immunity regulator, RIG-I.   It was specifically engineered for intravesical administration to elicit local stimulation of anti-tumor immune responses and drive durable efficacy in BCG-unresponsive NMIBC, while mitigating the risk of systemic toxicities from immune stimulation. The nanoparticle formulation can be handled without onerous administration and decontamination procedures for clinicians or patients.

Methods:

Three escalating doses of EG-70 were administered on two schedules at study Weeks 1 and 2 to BCG-unresponsive patients with carcinoma in situ (CIS) in the12-week Phase1 portion of the clinical trial (LEGEND).  Dose level 2 (DL2) had an additional cohort where dose instillations were given on Weeks 1, 2, 5 and 6.  After completing the 12-week study, patients with complete response (CR) or stable disease (SD) were allowed to remain on EG-70 for up to 3 additional 12-week cycles.  The primary objective was safety and tolerability, with efficacy being a secondary objective.

Results:

Twenty-four patients have received at least one dose of EG-70, with a total of 175 doses administered. No dose limiting toxicities (DLTs) required de-escalation of any doses.  There were 123 Grade 1and 2 adverse events, consistent with instravesical instrumentation.  There were   3 Grade 3 adverse events consider unrelated to study drug, and one Grade 3 event considered possibly related. 

Twenty-two patients are evaluable for efficacy, with 15/22 (68%) experiencing a CR at 3 months, with an additional 1/22 (5%) achieving CR at some point on treatment.  There were 18/22 patients that elected to receive additional treatment cycles after Month 3. Durable CRs were seen at all dose levels.  All efficacy assessments (including elective cycles 2-4) that have been completed to date are summarized in the figure below.

Conclusion:

The safety and tolerability profile of EG-70, intravesical non-viral immunotherapy, as well as the preliminary efficacy results are encouraging. The pivotal Phase 2 LEGEND study of EG-70 in BCG unresponsive high risk non-muscle invasive bladder cancer is currently active and enrolling patients.   

Funding: enGene, Inc