On November 3, 2024 Ferring Pharmaceuticals reported it has advanced three studies in the ADSTILADRIN (nadofaragene firadenovec-vncg) clinical trial program – two studies in patients with non-muscle invasive bladder cancer (NMIBC), and one study in patients with upper tract urothelial cancer (UTUC) (Press release, Ferring, DEC 3, 2024, View Source [SID1234648778]). The Company also announced researchers will present at the 25th Annual Meeting of the Society of Urologic Oncology (SUO) the study protocol for patients with intermediate-risk NMIBC and additional data from a Phase 3, open-label study demonstrating clinically meaningful cystectomy-free survival (CFS) after five years among patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive NMIBC who achieved an initial complete response at three months with ADSTILADRIN.
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ADSTILADRIN is the first and only intravesical non-replicating gene therapy approved by the U.S. Food and Drug Administration (FDA) in patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors (±Ta/T1).
Study sites in the U.S. were activated for two studies in the ABLE (ADSTILADRIN in BLadder CancEr) clinical trial program in NMIBC:
The three-arm, Phase 2 ABLE-22 (NCT06545955) trial is assessing the efficacy and safety of ADSTILADRIN as a monotherapy and as part of combination with chemotherapy or an immune checkpoint inhibitor for high-risk BCG-unresponsive NMIBC. Investigators in all three arms of the ABLE-22 study will have the option to re-induce appropriate patients who do not achieve a complete response to the initial single dose or combination regimen, an option that was not included in the original Phase 3 study.
The Phase 3B ABLE-32 (NCT06510374) trial is assessing the efficacy and safety of ADSTILADRIN in intermediate-risk NMIBC (IR NMIBC), for which there are no U.S. FDA-approved treatment options.
Ferring also initiated the LUNAR (Low-Grade UTUC Treated with Nadofaragene firadenovec Administered to Renal Pelvis) study (NCT06668493), a Phase 1-2, multi-center, multi-national, open-label, single-arm, repeat dose clinical trial evaluating the safety, tolerability, and efficacy of ADSTILADRIN instilled to the renal pelvis in patients with low-grade UTUC (LG UTUC).
"The availability of an innovative locally delivered gene therapy has the potential to be organ sparing for appropriate NMIBC and UTUC patients. The extension of the ADSTILADRIN clinical trial program – with a focus on IR NMIBC and LG UTUC where there is a desperate need for new treatments, and generation of mono and combination therapy data, including re-induction, for high-risk BCG-unresponsive NMIBC – is key to understanding how ADSTILADRIN may be able to help even more patients," said Joern Jakobsen, M.D., Ph.D., Vice President and Head of Global Research and Medical for Uro-Oncology and Urology, Ferring Pharmaceuticals. "We are pleased to have these studies underway to build on the evidence reported in the original Phase 3 study. Formalizing the collection of re-induction data in patients who do not achieve a complete response at their first three-month assessment also will add to our pursuit of strategies to potentially offer more patients the opportunity to preserve their bladder and avoid radical surgery."
About ADSTILADRIN Poster Presentations at SUO
ADSTILADRIN poster titles and presentation times at the SUO 2024 Annual Meeting, December 4-6, are:
Incidence and Pathologic Outcomes of Cystectomy in Patients With Bacillus Calmette-Guérin-Unresponsive Non-Muscle Invasive Bladder Cancer With Carcinoma In Situ Following Treatment With Nadofaragene Firadenovec-vncg, Poster #215, Friday, December 6 from 10:00-11:00 a.m. CST
ABLE-32: A Randomized, Controlled, Phase 3B Clinical Trial of Nadofaragene Firadenovec-vncg Versus Observation in Patients With Intermediate-Risk Non–Muscle-Invasive Bladder Cancer, Poster #232, Friday, December 6 from 1:45-2:45 p.m. CST
About the ADSTILADRIN Clinical Trial Program
Results from the final analysis of the 60-month follow-up data from the pivotal ADSTILADRIN Phase 3 clinical trial were announced earlier this year. Re-induction in patients who did not achieve a complete response at three months after a single initial dose was not included in the protocol.1
"The original Phase 3 study design was purposefully conservative and only allowed patients who demonstrated a complete response at three months to continue quarterly treatment with ADSTILADRIN as investigators confirmed the overall safety with low risk of progression of gene therapy in this patient population," said Colin P.N. Dinney, M.D., Chairman of the Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, and a lead investigator of the Phase 3 study. "The ADSTILADRIN Phase 3 clinical trial transformed our understanding of the treatment of patients with BCG-unresponsive NMIBC and paved the way to allow re-induction in subsequent studies."
Earlier this quarter, Ferring decided to prioritize collection of ADSTILADRIN re-induction data in patients with high-risk BCG-unresponsive NMIBC who did not have a complete response to the initial single dose of ADSTILADRIN through data sources within the clinical setting, including ABLE-22 and ABLE-41 (NCT06026332), and discontinued the previously announced ABLE-42 clinical trial. The ABLE-41 study – currently enrolling patients – is exploring early utilization, experiences, and outcomes of ADSTILADRIN in the routine care setting in high-risk BCG-unresponsive NMIBC patients.
"The approval of ADSTILADRIN and its successful launch has transformed the treatment landscape for BCG-unresponsive NMIBC patients, offering them new hope for durable bladder preservation. We hope to see efficacy together with the same low treatment burden and manageable safety profile for ADSTILADRIN in IR NMIBC and as part of combination therapy in BCG-unresponsive NMIBC," said Bipin Dalmia, Global Head of Uro-Oncology & Urology Franchise, Ferring Pharmaceuticals. "Expanding our program within NMIBC and also to UTUC with the LUNAR study is another step forward in our leadership journey to establish ADSTILADRIN as the new standard of care and the backbone therapy for patients across the urothelial cancer disease spectrum."
About the ABLE and LUNAR Clinical Trials
ABLE-22 is a Phase 2, randomized, multi-center, open-label three-arm trial evaluating the efficacy and safety of ADSTILADRIN as a monotherapy or in combination with chemotherapy (gemcitabine and docetaxel) or an immune checkpoint inhibitor (pembrolizumab) in adult patients with high-grade BCG-unresponsive NMIBC. High-grade tumors are more likely to grow and spread quickly. The study’s primary endpoint is a complete response (defined as absence of low- and high-grade disease) at month 3 (or month 6 for re-induced patients). Appropriate patients in all three treatment arms of ABLE-22 who do not have a complete response to the first three-month assessment will have the potential to receive re-induction with a second quarterly dose of ADSTILADRIN.
ABLE-32 is a Phase 3B, randomized, controlled trial assessing the potential efficacy and safety of ADSTILADRIN in patients with IR NMIBC. More than 450 participants from 100 global sites are expected to be enrolled and will either receive quarterly doses of ADSTILADRIN or undergo continued observation following transurethral resection of bladder tumor (TURBT) within 60 days prior to randomization. The primary efficacy endpoint is recurrence-free survival (RFS), from baseline to first documented recurrence, progression, or death, whichever occurs first during the treatment period.
ABLE-41 is an ongoing, multi-center, non-interventional, real-world evidence (RWE) study following patients with NMIBC aged 18 years or older who are being treated with ADSTILADRIN in a clinical setting and had not previously received this therapy in a clinical trial. The study is exploring early utilization, experiences, and outcomes of ADSTILADRIN in the routine care setting, including re-induction with a second quarterly dose in patients without a complete response to the initial single dose. The first patient was enrolled in September 2023.
LUNAR is a Phase 1-2 single-arm, open label trial evaluating the safety, tolerability, and efficacy of ADSTILADRIN in patients with low-grade UTUC. A safety lead-in period will be conducted for the first six patients. Absence of UTUC in the renal pelvis at months 3 or 6 will be defined as a complete response. Duration of response up to month 30 will be defined as the time from first achieved complete response to disease recurrence, progression to high-grade disease or disease-specific death, whichever occurs first.
About ADSTILADRIN
ADSTILADRIN (nadofaragene firadenovec-vncg) is the first and only FDA-approved intravesical non-replicating gene-therapy for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. It is a non-replicating adenovirus vector-based therapy containing the gene interferon alfa-2b, administered locally as a monotherapy by catheter directly into the bladder once every three months. The vector enters the cells of the bladder wall, releasing the active gene and causing the bladder’s cell walls to secrete high and transient local expression of interferon alfa-2b protein, a naturally occurring protein the body uses to fight cancer. This approach essentially turns the bladder wall cells into interferon microfactories, enhancing the body’s own natural defenses against the cancer.
ADSTILADRIN has been studied in a clinical trial program that includes 157 patients with high-risk, BCG-unresponsive NMIBC who had been treated with adequate BCG previously and did not see benefit from additional BCG treatment (full inclusion criteria published on clinicaltrials.gov: NCT02773849).2
Ferring is leading the future in uro-oncology treatment with ADSTILADRIN at the center, while expanding access with the support of new, state-of-the-art manufacturing facilities. As announced in January 2024, ADSTILADRIN is fully available and accessible in the U.S. ADSTILADRIN has confirmed 99 percent coverage for commercial and government-insured patients. As of April 1, 2024, in accordance with the Centers for Medicare and Medicaid Services (CMS), ADSTILADRIN established an Average Sales Price (ASP). Since the establishment of ASP, all covered claims submitted for reimbursement have received payment within an average of 25 days.3
Ferring is committed to investing in novel therapies, developing life-changing solutions that address unmet medical needs, and aiding the uro-oncology community in helping patients live better lives. More information is available in the U.S. at the dedicated Ferring Uro-Oncology channel on LinkedIn.
About Non-Muscle Invasive Bladder Cancer (NMIBC)
NMIBC is a form of bladder cancer that is found in the inner layer cells of the bladder and does not invade into or beyond the muscle wall.4 In the United States, bladder cancer is the sixth most common cancer,5 fourth among men,6 and it is estimated that there will be approximately 83,190 new cases of bladder cancer in the U.S. in 2024.6 Historically, 75% of bladder cancer presents as NMIBC.7 In patients with high-risk NMIBC, intravesical BCG remains the first-line standard-of-care. However, approximately one third of patients with NMIBC will not respond to BCG therapy and 50% of those with an initial response will experience recurrence or progression of their disease.8 Current treatment options for BCG-unresponsive patients are very limited, and National Comprehensive Cancer Network (NCCN) guidelines recommend cystectomy (partial or complete removal of the bladder).9
About Low-Grade Upper Tract Urothelial Cancer (UTUC)
UTUC accounts for about 10 percent of all urothelial cancers – cancer of the lining within the kidneys, bladder, or ureters – with the majority occurring in the lower tract or bladder.10 Clinicians use several standardized assessment and clinical staging methods to risk-stratify patients into "low" or "high" risk for progression to identify patients who are most likely to benefit from kidney-sparing treatment.10 Tumors that block the ureter or kidney can cause hydronephrosis (swelling of the kidney), infections, and impairment of kidney function.10 Low-grade tumors comprise all low-risk and some high-risk tumors in UTUC with management goals including treatment of visible tumors and preservation of the urinary tract.10 There is an estimated total incidence of just over 7,000 new UTUC cases each year in the U.S.,10 and the prevalence appears to be increasing.11
INDICATION
ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS: ADSTILADRIN is contraindicated in patients with prior hypersensitivity reactions to interferon alfa or to any component of the product.
WARNINGS AND PRECAUTIONS:
Risk with delayed cystectomy: Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy.
Risk of disseminated adenovirus infection: Persons who are immunocompromised or immunodeficient may be at risk for disseminated infection from ADSTILADRIN due to low levels of replication-competent adenovirus. Avoid ADSTILADRIN exposure to immunocompromised or immunodeficient individuals.
DOSAGE AND ADMINISTRATION: Administer ADSTILADRIN by intravesical instillation only. ADSTILADRIN is not for intravenous use, topical use, or oral administration.
USE IN SPECIFIC POPULATIONS: Advise females of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 3 months after the last dose.
ADVERSE REACTIONS: The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination urgency), creatinine increased, hematuria (blood in urine), phosphate decreased, chills, pyrexia (fever), and dysuria (painful urination).
You are encouraged to report negative side effects of prescription drugs to FDA. Visit www.FDA.gov/medwatch or call 1-800-332-1088. You may also contact Ferring Pharmaceuticals at 1-888-FERRING.