On April 27, 2025 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported results from the Phase 3 KEYNOTE-689 trial evaluating KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, as a perioperative treatment regimen for patients with stage III or IVA, resected, locally advanced head and neck squamous cell carcinoma (LA-HNSCC) (Press release, Merck & Co, APR 27, 2025, View Source [SID1234652189]). Results at the first interim analysis of the trial showed KEYTRUDA significantly improved event-free survival (EFS) as part of a perioperative treatment regimen with adjuvant standard of care (SOC) radiotherapy with or without cisplatin compared to adjuvant standard of care (SOC) radiotherapy with or without cisplatin alone in patients with resectable LA-HNSCC. These data are being presented for the first time today during a Plenary Session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 (Abstract #CT001) and were selected for the AACR (Free AACR Whitepaper) press program.

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After a median follow-up of 38.3 months (range, 9.0-66.5), treatment with KEYTRUDA before surgery (neoadjuvant), then continued in combination with standard of care radiotherapy (with or without cisplatin) after surgery followed by KEYTRUDA alone (adjuvant), reduced the risk of EFS events by 34% (HR=0.66 [95% CI, 0.49-0.88]; p=.0022) in the combined positive score (CPS) ≥10 population, by 30% (HR=0.70 [95% CI, 0.55-0.89; p=.0014) in the CPS ≥1 population and by 27% (HR=0.73 [95% CI 0.58-0.92]; p=.0041) in the intent-to-treat (ITT) population, compared to adjuvant radiotherapy (with or without cisplatin) alone in the ITT population. Among the CPS ≥10 population, median EFS was 59.7 months in the KEYTRUDA plus SOC group (95% CI, 41.1-not reached) versus 26.9 months (95% CI, 18.3-51.5) in the SOC group. Among the CPS ≥1 population, median EFS was 59.7 months (95% CI, 37.9-not reached) in the KEYTRUDA plus SOC group versus 29.6 months (95% CI, 19.5-41.9) in the SOC group. In the ITT population, median EFS was 51.8 months (95% CI, 37.5-not reached) in the KEYTRUDA plus SOC group versus 30.4 months (95% CI, 21.8-50.1) in the SOC group. The safety profile of KEYTRUDA was consistent with that observed in previously reported studies; no new safety signals were identified.

"As the first positive trial in over two decades for patients with resectable, locally advanced head and neck squamous cell carcinoma, the presentation of these landmark results marks an important moment for these patients and those who care for them," said Dr. Ravindra Uppaluri, the study’s co-principal investigator, director of Head and Neck Surgical Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute. "KEYNOTE-689 represents a meaningful development with a potential to provide an option that helps certain patients with LA-HNSCC reduce the risk of recurrence and disease progression earlier in their treatment journey."

"The addition of immunotherapy using KEYTRUDA to standard of care surgery and adjuvant (chemo)radiotherapy resulted in a significant reduction in the risk of event-free survival events by 27%, compared with standard of care therapy alone," said study co-principal investigator Dr. Douglas Adkins, Professor, Division of Oncology, Washington University School of Medicine in St. Louis. "These results are notable as they mark the first time an anti-PD-1 therapy has demonstrated a statistically significant and clinically meaningful improvement in event-free survival in the neoadjuvant and adjuvant setting in earlier stages of head and neck squamous cell carcinoma."

The study also showed a statistically significant improvement in major pathological response (mPR) rate, a key secondary endpoint, in patients with CPS ≥10 (difference in mPR rates: 13.7% [95% CI, 9.7-18.7]; p<0.00001), CPS ≥1 (9.8% [95% CI, 7.0-13.3]; p<0.00001) and in the ITT population (9.3% [95% CI, 6.7–12.8, P<.00001), compared to adjuvant radiotherapy alone.

A trend toward improvement in overall survival (OS), another key secondary endpoint, was observed in patients with CPS ≥10 (HR=0.72 [95% CI, 0.52-0.98]) at the time of this interim analysis for the KEYTRUDA plus standard of care regimen versus standard of care alone. The OS results did not reach statistical significance at the time of this interim analysis. Due to the statistical testing hierarchy, formal testing was not performed in the CPS ≥1 and ITT populations. OS will be evaluated at the next interim analysis.

"As the 12th positive pivotal trial for a KEYTRUDA-based regimen in earlier-stage cancers, the results from KEYNOTE-689 are a testament to our commitment to address an unmet need in this important area of research," said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. "These compelling results illustrate the potential of this regimen to change the landscape of care for certain patients facing this challenging disease. We are working with the FDA and other global authorities to bring this new option to patients as quickly as possible."

A supplemental Biologics License Application (sBLA) for KEYTRUDA based on data from KEYNOTE-689 is under priority review with the U.S. Food and Drug Administration (FDA), with a Prescription Drug User Fee Act (PDUFA), or target action, date of June 23, 2025.

KEYTRUDA is currently approved as monotherapy and in combination regimens for appropriate patients with metastatic or unresectable, recurrent HNSCC in the U.S., Europe, China, Japan and other countries around the world. For more information, please see the "Selected KEYTRUDA (pembrolizumab) Indications in the U.S." section below.

Study design and additional data from KEYNOTE-689

KEYNOTE-689 is a randomized, active-controlled, open-label Phase 3 trial (ClinicalTrials.gov, NCT03765918) evaluating KEYTRUDA as neoadjuvant treatment and KEYTRUDA in combination with standard of care radiotherapy (with or without cisplatin) as adjuvant treatment in treatment-naïve patients with newly diagnosed, stage III or IVA resectable, locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Efficacy outcomes are classified by programmed cell death ligand 1 (PD-L1) combined positive score (CPS) status. The primary endpoint is EFS, which is defined as the time from randomization to the first occurrence of radiographic disease progression; local or distant progression or recurrence; or death due to any cause. The secondary endpoints include OS, mPR, pathological complete response and safety. The study enrolled 714 patients who were randomized 1:1 to receive:

KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W] for two cycles) as neoadjuvant therapy prior to surgery, followed by either KEYTRUDA (200 mg IV Q3W for 15 cycles) plus standard of care radiotherapy with cisplatin (100 mg/m2 IV Q3W for three cycles) as adjuvant therapy following surgery for high-risk patients or KEYTRUDA (200 mg IV Q3W for 15 cycles) plus standard of care radiotherapy without cisplatin as adjuvant therapy following surgery for low-risk patients; or
No neoadjuvant therapy prior to surgery, followed by adjuvant standard of care radiotherapy with cisplatin (100 mg/m2 IV Q3W for three cycles) as adjuvant therapy following surgery for high-risk patients or standard of care radiotherapy without cisplatin as adjuvant therapy following surgery for low-risk patients.
The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 44.6% of patients receiving KEYTRUDA plus standard of care radiotherapy versus 42.9% of patients receiving standard of care radiotherapy alone. TRAEs led to death in 1.1% of patients receiving the KEYTRUDA regimen (n=4) and 0.3% of patients receiving standard of care radiotherapy (n=1). No new safety concerns were identified. Immune-mediated adverse events (AEs) of any grade occurred in 43.2% of patients receiving the KEYTRUDA regimen, most commonly hypothyroidism (24.7%).

About head and neck cancer

Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is cancer that has grown outside the original location, but has not yet spread to distant parts of the body. There are several factors that greatly increase the risk of developing head and neck cancer, including tobacco and alcohol use and human papillomavirus (HPV). It is estimated there were more than 947,200 new cases of head and neck cancer diagnosed and over 482,400 deaths from the disease in 2022 globally. In the U.S., it is estimated there will be approximately 72,680 new cases of head and neck cancer diagnosed and more than 16,680 deaths from the disease in 2025.

On April 27, 2025 ImmVira reported the Phase I clinical results of its oncolytic Herpes Simplex Virus ("oHSV") product MVR-C5252 targeting malignant glioma through poster presentation at American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") annual meeting (Press release, Immvira, APR 27, 2025, View Source [SID1234652208]).

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According to industry data, malignant glioma, a highly aggressive and recurrent brain cancer, has a five-year survival rate of less than 5%. Developed on ImmVira’s proprietary OVPENS platform, MVR-C5252 is specifically engineered with designed attenuation to achieve on-target malignant gliocyte killing and armed with PD-1 antibody and IL-12, for the synergistic anti-tumor effects of "oncolysis + immune activation". This innovative product has obtained Investigational New Drug approval in both the U.S. and China, as well as Orphan Drug Designation from the FDA.

The Phase I trial, for which the clinical study results were released, was conducted in collaboration with Duke University, a renowned institution with expertise in oncolytic virotherapy, immunotherapy, and CNS treatments. Unlike the commonly used Ommaya reservoir, MVR-C5252 is delivered intracranially via convection-enhanced delivery ("CED"). This approach can provide slow and sustained positive pressure to the target brain area via an implanted catheter to ensure even drug distribution, enabling multiple dosing while bypassing the blood-brain barrier. To date, five patients with recurrent high-grade glioma have received MVR-C5252 treatments.

In Stage 1A of the study, three patients received 5×10⁶ PFU and completed the dose-limiting toxicity ("DLT") period. Serial cytokine analysis of cerebrospinal fluid ("CSF") showed dynamic immune responses and intended biologic activity, with measurable changes in cytokine concentrations post-infusion. In addition, no serious adverse events ("SAEs"), DLTs, or Grade 3–5 adverse events ("AEs") occurred. The only reported Grade 1–2 AEs included fatigue, flu-like symptoms, and cognitive disturbance, indicating a favorable safety profile of MVR-C5252 delivered via CED.

Dr. Grace Guoying Zhou, ImmVira’s Chairwoman and CEO, said, "We are committed to developing advanced therapies featuring novel modalities using oHSV and engineered exosomes, to address complex and challenging diseases. After years of parallel development and in-depth explorations in both the U.S. and China, we have strategically focused on malignant glioma for the development of MVR-C5252, leveraging HSV-1’s unique biological and translational medical characteristics and in line with highly unmet medical needs and substantial market potential. Our collaboration with Duke University, a global leader in glioma research and treatment, will accelerate clinical development of this innovative therapy, delivering a new solution for this type of severe life-threatening diseases."

On April 27, 2025 Nona Biosciences, a global biotechnology company providing integrated solutions from "Idea to IND" (I to ITM), reported that its partner, Pfizer, has presented preclinical data on PF-08052666 (HBM9033; SGN-MesoC2), a first-in-class topoisomerase 1 inhibitor (TOP1i)-based antibody-drug conjugate (ADC) targeting mesothelin (MSLN), at the AACR (Free AACR Whitepaper) Annual Meeting 2025 (Press release, Nona Biosciences, APR 27, 2025, View Source [SID1234652190]). This ADC was originally developed using Nona Biosciences’ proprietary Harbour Mice and integrated ADC platforms. Pfizer acquired its global clinical development and commercialization rights on December 14, 2023.

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Poster Presentation at AACR (Free AACR Whitepaper) Annual Meeting 2025

Title: PF-08052666 (HBM9033), a first-in-class topoisomerase 1 inhibitor-based ADC targeting MSLN, demonstrates potent antitumor activity in preclinical models of ovarian, lung, and colorectal cancers

Abstract Number: 324

Poster Board Number: 16

Session Title: Antireceptors and Other Biological Therapeutic Agents

Session Date: April 27, 2025

PF-08052666 was designed to address the limitations of earlier anti-MSLN ADCs through a novel antibody, differentiated linker-payload, and a higher drug-to-antibody ratio (DAR). It consists of a human IgG1 monoclonal antibody conjugated to a potent camptothecin-based TOP1i payload with a protease-cleavable linker, achieving an average DAR of 8.

Key Preclinical Findings Presented at AACR (Free AACR Whitepaper) Annual Meeting 2025

In vitro, PF-08052666 demonstrated direct cytotoxicity through delivery of payload to MSLN-positive cells, bystander killing activity on co-cultured MSLN-negative cells, and maintained cytotoxicity even in the presence of physiologically relevant concentrations of soluble MSLN.
In vivo, PF-08052666 outperformed a DM4-based anti-MSLN benchmark ADC in both cell-line and patient-derived xenograft models across multiple tumor types, including ovarian, lung, and colorectal cancers.
PF-08052666 also outperformed the DM4-based anti-MSLN benchmark ADC in heterogeneous xenograft models consisting of ad-mixed MSLN-positive and MSLN-negative cells, demonstrating the increased bystander activity of the novel linker-payload of MesoC2.
These promising preclinical results support the ongoing first-in-human phase 1 clinical trial of PF-08052666 in patients with advanced solid tumors (NCT06466187), which is currently enrolling participants.

"The preclinical data on PF-08052666 presented by Pfizer at AACR (Free AACR Whitepaper) 2025 reflects the strength of our technology platforms and our dedication to advancing transformative therapies," said Jingsong Wang, MD, PhD, Chairman of Nona Biosciences. "By leveraging our industry-leading technology platforms, we continue to drive innovation that enables the development of next-generation biotherapeutics. We look forward to further collaboration with Pfizer to accelerate breakthroughs that address critical medical needs."

About PF-08052666 (HBM9033)

PF-08052666 is an ADC drug that targets human MSLN, a tumor-associated antigen (TAA) upregulated in various solid tumors. The fully human monoclonal antibody (mAb) in PF-08052666 is derived from the Harbour Mice platform and possesses well-tuned properties, exhibiting reduced binding to soluble MSLN while maintaining strong binding and internalization to membrane-bound MSLN. The unique design of the mAb was created to enhance potency in various preclinical tumor models with differing MSLN expression levels, positioning PF-08052666 as a potential globally best-in-class therapeutic option.

On April 26, 2025 Protara Therapeutics, Inc. (Nasdaq: TARA), a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases, reported updated results from its ongoing Phase 2 open-label ADVANCED-2 trial assessing intravesical TARA-002, the Company’s investigational cell-based therapy, in high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) patients with carcinoma in situ, or CIS (± Ta/T1), who are Bacillus Calmette-Guérin (BCG)-Unresponsive or BCG-Naïve (Press release, Protara Therapeutics, APR 26, 2025, View Source [SID1234652191]). The results will be featured today during an interactive poster session at the American Urological Association 2025 Annual Meeting in Las Vegas.

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"For patients with high-risk NMIBC, there are few effective and durable therapies available other than radical cystectomy, which we know is quite difficult for patients to tolerate," said Tom Jayram, M.D., Director of the Advanced Therapeutics Center at Urology Associates, and ADVANCED-2 study investigator. "TARA-002 has shown impressive efficacy, safety profile, and 12-month durability in its Phase 2 trial. In the clinic, we have seen TARA-002 become easily integrated into workflow without major hurdles for the patients or staff. This combination of clinical activity and ease of use makes me optimistic about TARA-002 having a meaningful impact in clinical practice."

Interim Results

BCG-Unresponsive Cohort

The BCG-Unresponsive dataset includes a total of five patients, all of whom were six- and nine-month evaluable, and three of whom were evaluable at 12 months as of an April 16, 2025 data cutoff.

The complete response (CR) rate at any time in BCG-Unresponsive patients was 100% (5/5).
The CR rate in BCG-Unresponsive patients was 100% (5/5) at six months, 80% (4/5) at nine months, and 67% (2/3) at 12 months.
BCG-Naïve Cohort

The BCG-Naïve dataset includes a total of 21 patients, including 16 evaluable at six months, eight at nine months, and seven at 12 months as of an April 16, 2025 data cutoff.

The CR rate at any time in BCG-Naïve patients was 76% (16/21).
The CR rate in BCG-Naïve patients was 63% (10/16) at six months, 63% (5/8) at nine months, and 43% (3/7) at 12 months.
Safety

The majority of adverse events were Grade 1 and transient with no Grade 3 or greater treatment-related adverse events (TRAEs) as assessed by study investigators. No patients discontinued treatment due to TRAEs. The most common adverse events were in line with typical responses to bacterial immunopotentiation, such as flu-like symptoms. The most common urinary symptoms reflect urinary tract instrumentation effects, such as bladder spasm, burning sensation, and urinary tract infection. Most bladder irritations resolved shortly after administration or within a few hours to a few days.

"The durable results shared today continue to support our conviction that TARA-002 has the potential to make a meaningful difference in the lives of patients with NMIBC," said Jesse Shefferman, Chief Executive Officer of Protara Therapeutics. "Notably, we are particularly pleased with the competitive 12-month CR rates observed in the registrational BCG-Unresponsive cohort as well as the BCG-Naïve cohort. We look forward to continuing to advance this important trial as we work toward our mission of bringing transformative therapies to patients."

The Company continues to expect to present an interim update with results from approximately 25 six-month evaluable BCG-Unresponsive patients by the end of 2025.

Conference Call and Webcast

Protara will host a conference call and webcast to discuss the data on Monday, April 28, 2025, at 8:30 am ET. The live call can be accessed by registering as a participant here. Upon registration, participants will receive conference call dial-in information. A live webcast of the event can be accessed by visiting the Events and Presentations section of the Company’s website: View Source The webcast will be archived for a limited time following the presentation.

About ADVANCED-2

ADVANCED-2 (NCT05951179) is a Phase 2 open-label trial assessing intravesical TARA-002 in NMIBC patients with carcinoma in situ or CIS (± Ta/T1) who are Bacillus Calmette-Guérin (BCG)-Unresponsive (n≈100) and BCG-Naïve (n=31). The BCG-Unresponsive cohort has been designed to be registrational in alignment with the U.S. Food and Drug Administration’s 2024 BCG-Unresponsive Non-muscle Invasive Bladder Cancer: Developing Drugs and Biological Products for Treatment, Draft Guidance for Industry.

About TARA-002

TARA-002 is an investigational cell therapy in development for the treatment of NMIBC and of LMs, for which it has been granted Rare Pediatric Disease Designation by the U.S. Food and Drug Administration. TARA-002 was developed from the same master cell bank of genetically distinct group A Streptococcus pyogenes as OK-432, a broad immunopotentiator marketed as Picibanil in Japan by Chugai Pharmaceutical Co., Ltd. Protara has successfully shown manufacturing comparability between TARA-002 and OK-432.

When TARA-002 is administered, it is hypothesized that innate and adaptive immune cells within the cyst or tumor are activated and produce a pro-inflammatory response with release of cytokines such as tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma IL-6, IL-10, IL-12. TARA-002 also directly kills tumor cells and triggers a host immune response by inducing immunogenic cell death, which further enhances the antitumor immune response.

About Non-Muscle Invasive Bladder Cancer (NMIBC)

Bladder cancer is the 6th most common cancer in the United States, with NMIBC representing approximately 80% of bladder cancer diagnoses. Approximately 65,000 patients are diagnosed with NMIBC in the United States each year. NMIBC is cancer found in the tissue that lines the inner surface of the bladder that has not spread into the bladder muscle.

On April 26, 2025 UroGen Pharma Ltd. (Nasdaq: URGN), a biotech company dedicated to developing and commercializing innovative solutions that treat urothelial and specialty cancers, reported encouraging safety data from the Phase 1 dose-escalation study for UGN-301 (zalifrelimab) intravesical solution, an investigational drug in development for the treatment of recurrent non-muscle invasive bladder cancer (NMIBC) (Press release, UroGen Pharma, APR 26, 2025, View Source [SID1234652194]).

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"The early safety profile and clinical activity results from this study are encouraging," said Jay Raman, M.D., Professor and Chair of Urology, and Professor of Surgery, Penn State Cancer Institute, PA. "This innovative approach of localized drug delivery combined with immune modulation merits additional investigation in the treatment of non-muscle invasive bladder cancer."

The multi-part clinical study included up to 30 patients per arm, aimed to assess safety and determine the recommended Phase 2 dose of UGN-301 as monotherapy and in combination with other agents. In the monotherapy arm, dose escalation continued to the maximum feasible dose. No dose-limiting toxicities and no treatment-emergent adverse events leading to treatment discontinuation were observed. This study also demonstrated that local delivery of UGN-301 formulated in our proprietary reverse thermal gel (RTGel) allowed sustained exposure of zalifrelimab in the bladder with limited systemic exposure, which mitigated the risk of systemic immune-related toxicities associated with CTLA-4 inhibition.

With respect to clinical activity observed in the trial, among evaluable patients who received UGN-301, 46% (6 of 13) of those with Ta/T1 disease and 33% (2 of 6) of those with carcinoma in situ (CIS) ± Ta/T1 disease were recurrence-free or had achieved a complete response at week 12. Notably, 60% (3 of 5) of patients with Ta/T1 disease treated with 300 mg continued to remain recurrence-free at the 15-month disease assessment, including one patient with high-grade T1 disease. In the 500 mg cohort, 25% (1 of 4) of patients with CIS disease and 33% (1 of 3) of patients with Ta/T1 disease remained disease-free at six months, both of whom are still active participants in the study.

These findings highlight the potential of UGN-301 as a targeted treatment for NMIBC with an acceptable safety profile. Presentation of data from the combination arms is planned for later this year.

"Our hypothesis is that UGN-301’s unique formulation could potentially offer the dual benefits of maximizing therapeutic activity while minimizing systemic side effects, a key challenge in cancer immunotherapy," said Mark Schoenberg, Chief Medical Officer, UroGen. "Although this requires additional clinical investigation, we are encouraged by the potential of UGN-301 as an investigational treatment for patients with recurrent NMIBC."

About Non-Muscle Invasive Bladder Cancer and High-Grade Disease

In the U.S., bladder cancer is the second most common urologic cancer in men. Bladder cancer primarily affects older populations with increased risk of comorbidities, with the median age of diagnosis being 73 years. High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a serious and potentially life-threatening form of bladder cancer that remains confined to the inner layers of the bladder wall but exhibits aggressive behavior and a higher risk of progression. In the U.S., HG-NMIBC accounts for approximately 30–40% of all newly diagnosed NMIBC cases. Patients with HG-NMIBC face a significantly elevated risk of recurrence and progression to muscle-invasive disease, necessitating close surveillance and aggressive treatment. The standard of care includes complete transurethral resection of bladder tumor, often followed by intravesical therapy such as Bacillus Calmette-Guérin (BCG). However, BCG has a treatment failure rate of approximately 40-50%, leaving patients with limited treatment options short of radical cystectomy. Given the high recurrence and progression rates, HG-NMIBC presents a substantial clinical and quality-of-life burden. Upon recurrence, which occurs in approximately 70% of patients, the patients undergo another round of BCG therapy with a response rate of approximately 30%.

About UGN-301

UGN-301 is an anti-CTLA-4 monoclonal antibody (zalifrelimab), originally licensed from Agenus Inc. in 2019. It is formulated with RTGel, our proprietary reverse-thermal hydrogel, for intravesical administration into the bladder. Intravesical administration of UGN-301 is designed to increase drug concentrations in the bladder without significant systemic exposure, potentially diminishing the systemic toxicity associated with CTLA-4 blockade. UroGen is evaluating UGN-301 in a multi-arm Phase 1 study of UGN-301 as monotherapy and in combination with other agents. The safety of UGN-301 is being evaluated in the monotherapy arm of the study as combination therapy for HG-NMIBC.