enGene Tackles Nonmuscle-Invasive Bladder Cancer With Expansive Phase 1/2 LEGEND Trial for Gene Therapy EG-70

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With the company having recently announced that it intends to expand the clinical trial with a new cohort, CGTLive® has decided to take a closer look at this ongoing study.

enGene's EG-70 (detalimogene voraplasmid), an investigational nonviral immuno-oncology gene therapy intended to treat bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle-invasive bladder cancer (NMIBC), is currently being evaluated in the phase 1/2 LEGEND clinical trial (NCT04752722).1 With the company having recently announced that it intends to expand the trial with a new cohort, CGTLive® has decided to take a closer look at this ongoing study.

LEGEND began on April 22,2021. Led by study director Christine Tosone, MS, RAC, enGene, the vice president, head of clinical development operations at enGene, the multicenter clinical trial consists of a dose-escalation portion (phase 1) focused on safety and an efficacy-focused portion (phase 2). The phase 1 portion, which has now finished treating patients, took the form of a 3+3 dose-escalation, with patients receiving 0.25 mg/mL (dose level 1, DL1), 0.8 mg/mL (DL2), or 2.5 mg/mL (DL3) on a schedule of either 2 doses per 12-week cycle (at Day 1 and Day 8) or 4 doses per 12-week cycle (Day 1, Day 8, Day 29, and Day 36).2 The portion, which was open to patients with high-risk NMIBC with carcinoma in situ (CIS) for whom previous BCG was unsuccessful, treated 24 patients in total. The schedule selected for the phase 2 portion was 4 doses at DL2 delivered at Week 1, Week 2, Week 5, and Week 6 of 12-week cycles. The phase 2 portion is treating a cohort of patients with BCG-unresponsive NMIBC with CIS (cohort 1); a second cohort of patients with NMIBC with CIS who are BCG-naive or who have received inadequate BCG (see recently announced update below); and includes a planned third cohort for patients with high-risk BCG-unresponsive papillary-only NMIBC. In a June 2024 announcement, enGene stated that the third cohort in the phase 2 portion is expected to begin enrolling patients in Q4 of this year.1 The company also plans to modify the second cohort to separately enroll patients with NMIBC with CIS who are BCG-naïve and BCG-exposed in cohorts 2a and 2b, respectively. This expansion of the second cohort is also expected to begin enrolling patients in Q4 2024, and the company has paused enrollment in the second cohort until then.

“Our $200 million private placement in February positioned us well to execute our primary strategy of broadly developing EG-70 to be a patient- and practice-friendly option across a multitude of potential bladder cancer indications,” Jason Hanson, JD, the chief executive officer of enGene, said in a June 2024 statement.1 “Correspondingly, our planned initial expansion of the LEGEND study will include a cohort focused on enrollment of patients with high-risk, BCG-unresponsive papillary-only NMIBC, a disease with persistent unmet need for which EG-70 may be well-suited. Furthermore, we plan to provide the interim data for the LEGEND BCG-unresponsive cohort by the end of September 2024. We believe the design of EG-70, with its ease-of-use and nonviral profile, positions it well to seamlessly slot into the standard of care, with the goal of becoming a practice-changing product that does not require a change in practice for urologists.”

According to its clinicaltrials.gov page, which was most recently updated on June 20, 2024, LEGEND is expected to enroll up to 222 participants in total and has an estimated completion date of May 2027, with an estimated primary completion date of June 2025. The study is recruiting in US states including Arizona, California, Washington DC, Florida, Georgia, Kansas, Maryland, Michigan, Michigan, Minnesota, New Jersey, New York, North Carolina, Ohio, Oregon, South Carolina, Texas, and Wisconsin.

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The primary end point for the phase 1 portion of LEGEND consists of the nature, incidence, relatedness to treatment, and severity of all treatment-emergent adverse events (TEAEs) and serious TEAEs that occur during a 2-year timeframe. The phase 2 portion’s primary end points include the percentage of patients with a cystoscopic complete response (CR) at 48 weeks posttreatment, as assessed by the cystoscopy exam, urine cytology, bladder biopsies, and the nature, incidence, relatedness to treatment, and severity of TEAEs that occur during a 3-year timeframe. The phase 1 portion’s secondary end points include the number of patients who experienced a dose-limiting toxicity through the end of the first 12-week cycle and the CR rate as evaluated by cystoscopy at approximately 12 weeks posttreatment. The phase 2 portion’s secondary end points include the progression-free survival rate in a timeframe of approximately 3 years; the duration of response for patients who respond during a timeframe of approximately 3 years; a quality of life assessment carried out at 24 weeks posttreatment; and the CR rate at 12, 24, 36, and 96 weeks posttreatment.

LEGEND is open to patients aged 18 years and older. BCG-unresponsive patients with CIS must have experienced persistent disease within 12 months or a recurrence within 6 months of completing adequate BCG therapy—definitions consistent with the FDA’s definitions of BCG-unresponsive disease (2018). Patients who are BCG-naive or did not receive adequate BCG must have NMIMBC with current CIS of the bladder must have received either incomplete BCG consisting of at least 1 dose or have previously been treated with at least 1 dose of intravesical chemotherapy following transurethral resection of bladder tumor. All patients must have not undergone cystectomy and must have CIS documented or indicated by pathology.

Patients who have previously been treated unsuccessfully with an investigational or approved checkpoint inhibitor are eligible for inclusion in phase 1 at 30 days after treatment or in phase 2 at 3 months after treatment. Patients with T1 lesions enrolling in the phase 2 portion must have a screening biopsy that contains the muscularis layer. All patients in LEGEND must additionally have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; an absolute neutrophil count of more than 1,500/mm3; a hemoglobin level greater than 9.0 g/dL; a platelet count greater than 100,000/mm3; total bilirubin less than or equal to 1.5 times the upper limit of normal (ULN); aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels less than or equal to 2.5 times the ULN; adequate renal function with creatinine clearance greater than 30 mL/min; prothrombin time and partial thromboplastin time of less than or equal to 1.25 times the ULN or within the therapeutic range if the patient is on anticoagulation therapy; and satisfactory bladder function with the ability to retain EG-70 for a minimum of 60 minutes.

Patients with any malignancy besides NMIBC, basal/squamous cell skin cancers, or noninvasive cancer of the cervix that was diagnosed within 1 year of study entry or that has required therapy for active disease within the last 12 months and patients on concurrent treatment with any chemotherapeutic agent will be excluded from participation in LEGEND. Additional criteria for exclusion are treatment with any previous therapeutic agent within the 30 days before screening; evidence of metastatic disease or persistent or ongoing renal failure; participation in any other study for an investigational agent within 30 days prior to screening; any prior treatment of NMIBC with any investigational gene or immunotherapy agent; treatment with prostate brachytherapy within the last 12 months; active interstitial cystitis as observed by cystoscopy or biopsy; any active and uncontrolled infection requiring systemic therapy; any HIV, Hepatitis B, or Hepatitis C infection; significant cardiovascular risks such as coronary stenting within the past 8 weeks or myocardial infarction within the past 6 months; or hypersensitivity to any of the excipients of the study treatment. Patients with a history of partial cystectomy; unresolved vesicoureteral reflux or an indwelling urinary stent; unresolved hydronephrosis due to ureteral obstruction; external beam radiation to the pelvis; interstitial lung disease or pneumonitis in patients who have previously received a PD-1 or PD-L1 inhibitor therapy; or difficult catheterization that in the opinion of the investigator will prevent administration of EG-70 will also be ineligible to participate.

“enGene’s Phase 1/2 LEGEND study is designed to demonstrate the potential of EG-70 across a broad group of high-risk NMIBC patients, encompassing patients who are unresponsive to BCG as well as those who are naïve to BCG or were unable to receive a full course of treatment due to the ongoing global BCG shortage," Hanson said in a statement issued to CGTLive in June 2024. "In light of our recently announced decision to expand the study with a third cohort of patients who are BCG-unresponsive with high-risk papillary-only NMIBC, we believe LEGEND is well-positioned to generate a comprehensive dataset in support of EG-70’s use across a spectrum of high-risk NMIBC patients. Furthermore, EG-70 is a nonviral gene therapy candidate designed for straightforward intravesical administration at the point of care and to be well-suited for use in community- and high-volume urology clinics where the majority of NMIBC patients are treated. EG-70 has no thaw process, BSL2-like handling requirements, or pre- or post-treatment requirements for patients.”

EG-70 consists of a plasmid which encodes for IL-12, for the purpose of stimulating the adaptive immune system, and 2 RIG-I agonists, which are intended to stimulate the innate immune system.3,4 It is intravesically administered as a bladder instillation via catheter with a targeted retention time of 60 minutes. enGene recently presented data from the phase 1 portion of LEGEND at the American Urology Association 2024 Annual Meeting, held May 3-6, 2024 in San Antonio, TX.2

“EG-70 was rationally designed to be easy to use and meet the needs of patients and urologists alike," Hanson said in a May 2024 statement.5 "As a nonviral, noninfectious, locally delivered genetic medicine, EG-70 is designed to synergistically activate both the innate and adaptive immune responses, be easily reconstituted in water, and require only a short procedural time. Within the subgroup of patients in LEGEND’s phase 1 who received our optimized phase 2 dose, we saw complete response rates of 70% and 60% at 3 months and 6 months, respectively, which speak to EG-70’s potential to drive durable remissions. The encouraging safety data from the phase 1 study also suggest that this efficacy was achieved without significant impairment to the patients’ quality of life. We look forward to providing additional updates on the broader EG-70 program as we look to expand its potential use across bladder cancer.”

REFERENCES
1. enGene Reports Second Quarter 2024 Financial Results and Provides a Business Update. News release. enGene Holdings Inc. June 14, 2024. Accessed June 24, 2024. https://engene.com/engene-reports-second-quarter-2024-financial-results-and-provides-a-business-update/
2. Kalota S, Joshi S, Bui M, et al. LEGEND: a Phase 1/2 study of EG-70 (detalimogene voraplasmid), a novel, non-viral intravesical gene therapy for patients with BCG-unresponsive nonmuscle invasive bladder cancer with carcinoma in situ (CIS). Presented at: the American Urology Association 2024 Annual Meeting, held May 3-6, 2024 in San Antonio, TX.
3. Steinberg GD, Kalota SJ, Lotan Y, Warner L, Dauphinee, Mazanet R. Clinical results of a phase 1 study of intravesical EG-70 in patients with BCG-unresponsive NMIBC. Presented at: American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held in San Francisco, California, February 16-18, 2023. Abstract #512
4. enGene announces poster presentation containing interim Phase 1 clinical trial data at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. News release. enGene Inc. February 14, 2023. Accessed June 24, 2024. https://www.newswire.ca/news-releases/engene-announces-positive-preliminary-phase-1-2-data-with-eg-70-in-bcg-unresponsive-non-muscle-invasive-bladder-cancer-848397743.html
5. enGene to present details of its pivotal phase 1/2 LEGEND study of EG-70 in bcg-unresponsive non-muscle invasive bladder cancer with carcinoma in situ at the american urology association 2024 annual meeting. News release. enGene Holdings Inc. May 2, 2024. Accessed June 24, 2024. https://engene.com/engene-to-present-details-of-its-pivotal-phase-1-2-legend-study-of-eg-70-in-bcg-unresponsive-non-muscle-invasive-bladder-cancer-with-carcinoma-in-situ-at-the-american-urology-association-2024-annual-m/
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