Cretostimogene Grenadenorepvec (CG0070): An Oncolytic Immunotherapy for Bladder Cancer

I. Introduction to CG0070 (Cretostimogene Grenadenorepvec)

A. Overview and Investigational Status

Cretostimogene grenadenorepvec, also widely known by its investigational identifier CG0070, is an advanced oncolytic immunotherapy currently undergoing late-stage clinical development. Its primary therapeutic focus is the treatment of bladder cancer, with a significant emphasis on Non-Muscle Invasive Bladder Cancer (NMIBC).[1] The agent is being developed by CG Oncology, a biopharmaceutical company dedicated to urologic oncology.[4] CG0070 is formulated as a solid preparation intended for intravesical administration directly into the bladder.[6] This local delivery mechanism is a key feature of its therapeutic strategy.

The concurrent use of the alphanumeric identifier "CG0070" and the more formal proposed non-proprietary name "Cretostimogene Grenadenorepvec" in recent scientific literature and company communications [1] reflects the agent's progression through the clinical development pipeline. Typically, investigational compounds are initially designated by such codes. As a drug advances to late-stage trials and approaches potential regulatory submission, a non-proprietary (generic) name is adopted. This transition facilitates standardized communication among healthcare professionals, regulatory bodies, and the broader scientific community, and is a recognized marker of developmental maturity towards potential commercialization.

B. Drug Identification

For standardized referencing, Cretostimogene Grenadenorepvec is cataloged in the DrugBank database under the accession number DB05148.[6]

C. Clarification of Drug Classification: Oncolytic Virus (Biologic)

It is critical to address and correct a misclassification noted in some background descriptions that refer to CG0070 as a "Small Molecule." Extensive evidence from peer-reviewed publications and clinical trial documentation unequivocally confirms that CG0070 is a replication-competent oncolytic adenovirus, specifically an adenovirus serotype 5 (Ad5)-based construct.[2] As such, CG0070 is classified as a biologic agent, not a small molecule. Oncolytic viruses represent a distinct and innovative class of therapeutic agents. They are engineered or naturally occurring viruses that selectively infect, replicate within, and ultimately destroy cancer cells through a process known as oncolysis. Beyond direct tumor cell killing, a crucial aspect of their therapeutic effect is the concurrent stimulation of a host anti-tumor immune response. This fundamental classification as an oncolytic virus is paramount for understanding its complex biological activity, manufacturing processes, regulatory pathway, mechanism of action, and clinical application, all of which differ substantially from those of traditional small molecule drugs.

The implications of this correct classification are profound. Small molecule drugs typically exert their effects by interacting with specific molecular targets through well-defined chemical interactions. In contrast, oncolytic viruses like CG0070 possess multifaceted mechanisms of action that involve not only viral replication and direct cell lysis but also a complex engagement and modulation of the host's immune system. The manufacturing and characterization of biologics, particularly viral vectors, are significantly more intricate and demanding than for conventional small molecules due to their inherent structural complexity and biological nature. Furthermore, the regulatory approval pathway for biologics (e.g., a Biologics License Application - BLA in the United States) is distinct from that for small molecules (New Drug Application - NDA). Pharmacokinetic and pharmacodynamic (PK/PD) considerations also differ markedly; for oncolytic viruses, viral kinetics, biodistribution, persistence, and the nature of the induced immune responses are critical parameters, unlike the typical absorption, distribution, metabolism, and excretion (ADME) profiles assessed for small molecules.

II. Mechanism of Action

A. Dual Mechanism of Action: A Synergistic Anti-Cancer Strategy

Cretostimogene grenadenorepvec employs a sophisticated, dual-pronged mechanism to combat cancer, designed to achieve a more comprehensive and potentially durable therapeutic effect than either modality alone. This strategy involves: 1) direct, selective oncolysis of tumor cells, leading to their destruction, and 2) the stimulation of a robust, systemic anti-tumor immune response, significantly mediated by the virus's engineered expression of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF).[2] This dual action—direct tumor kill coupled with immune activation—is a hallmark of advanced oncolytic immunotherapy design. As stated by CG Oncology, "Cretostimogene grenadenorepvec is an oncolytic immunotherapy with a dual mechanism of action that selectively replicates in and lyses cancer cells while simultaneously amplifying the immune response against bladder tumors".[2]

B. Selective Oncolysis: Exploiting the Retinoblastoma (Rb) Pathway Defect

The tumor-selective replication of Cretostimogene Grenadenorepvec is a critical feature, engineered to target a common vulnerability in many cancer cells: defects in the Retinoblastoma (Rb) tumor suppressor pathway.[2] The Rb pathway plays a crucial role in regulating cell cycle progression, and its dysregulation is a frequent event in oncogenesis.

This selectivity is achieved through a specific genetic modification within the adenovirus. The expression of the E1A gene, which is essential for adenoviral replication, is placed under the control of a human E2F-1 promoter.[2] In normal, healthy cells with a functional Rb pathway, the activity of the E2F-1 transcription factor is tightly repressed by the Rb protein. Consequently, E1A expression is minimal, and viral replication is significantly restricted. Conversely, in many cancer cells, the Rb pathway is defective (e.g., due to mutations in the RB1 gene or genes encoding its upstream regulators like p16INK4a). This leads to constitutive activation or de-repression of E2F-1, which in turn drives high-level expression of the E1A gene from the viral genome. This robust E1A expression initiates the viral replication cycle, leading to the production of new viral particles and ultimately the lysis and death of the infected cancer cell.[2] This targeted replication is designed to maximize the anti-tumor effect while minimizing toxicity to normal tissues.

While the E2F-1 promoter design confers selectivity based on Rb-pathway defects, the clinical correlation between Rb status and response has shown some evolution. Early Phase I/II data indicated a potentially stronger correlation, with one report suggesting a 58% clinical response in patients with Rb pathway defects versus 20% in those with wild-type Rb.[9] However, a subsequent report on the BOND study mentioned that the correlation of defective Rb pathways and clinical response was "unclear".[9] This suggests that while Rb-pathway status is a foundational element for the virus's selective replication, it might not be the sole or a perfectly predictive biomarker for clinical efficacy. The complexity in definitively assessing "Rb defectiveness" across diverse patient tumors, potential variations in assay methodologies, or the significant contribution of the immune-mediated mechanism (which could be influenced by other factors in the tumor microenvironment and overall patient immune status) might contribute to this nuanced observation. Ongoing research, including exploratory biomarker assessments in current clinical trials such as the evaluation of E2F expression and immune infiltration [11], aims to further elucidate predictive markers of response.

C. Immune Stimulation: The Role of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)

Beyond its direct oncolytic capabilities, Cretostimogene Grenadenorepvec is engineered to enhance the host's anti-tumor immune response. It achieves this by carrying and expressing the gene for human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF).[2] GM-CSF is a potent hematopoietic growth factor and immune modulator. Its local expression at the tumor site, following viral infection and transgene expression, effectively transforms the tumor microenvironment into an in situ vaccine, acting as an adjuvant to amplify immune activity.[2]

The locally produced GM-CSF promotes the recruitment, maturation, proliferation, and functional activity of antigen-presenting cells (APCs), particularly dendritic cells and macrophages.[2] As tumor cells are lysed by the replicating virus (immunogenic cell death), they release a plethora of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). The GM-CSF-activated APCs efficiently capture and process these TAAs. These APCs then migrate to regional lymph nodes, where they present the processed antigens to T-lymphocytes, thereby initiating and amplifying a systemic, tumor-specific adaptive immune response. This immune-mediated killing, driven by tumor-specific T cells, complements the direct oncolytic effect and is hypothesized to contribute to more durable clinical responses and potentially control residual disease or micrometastases.[2]

The dual mechanism of CG0070—immediate tumor cell lysis by viral replication (an innate-like effect) followed by GM-CSF-driven antigen presentation leading to a T-cell mediated adaptive immune response—embodies a sophisticated immunological strategy. This has been described as facilitating an "innate to adaptive switching with immunogenic memory and a long immuno-oncology tail" [15], or a "postulated innate to adaptive immune switching".[16] This paradigm suggests that the therapy aims not just for initial tumor debulking but for the induction of lasting anti-tumor immunity. The initial viral oncolysis provides a rich source of tumor antigens and danger signals. The GM-CSF then acts as a crucial bridge, enhancing the ability of APCs to process these signals and effectively prime naive T cells in the lymph nodes. This leads to the generation of tumor-specific cytotoxic T lymphocytes (CTLs) and helper T cells, which can then traffic to the tumor site and potentially other sites of disease to mediate long-term tumor cell killing. The generation of this adaptive immunity and immunological memory is believed to be a key factor underpinning the durable responses observed in clinical trials, extending beyond the period of active viral replication.

D. Viral Entry Mechanism

Cretostimogene Grenadenorepvec is reported to initiate infection by binding to specific receptors on the surface of target cells. These include the Coxsackievirus and Adenovirus Receptor (CAR) and integrin αvβ5. These receptors are often found in specialized intracellular junctions, such as tight junctions, of polarized epithelial cells, including those lining the bladder urothelium.[2] The expression levels of these receptors on tumor cells can influence viral tropism and the efficiency of initial infection.

III. Preclinical Evidence

A. Foundational Studies in Bladder Cancer Models

The preclinical development of Cretostimogene Grenadenorepvec was substantially supported by foundational studies, most notably the work published by Ramesh et al. in 2006, which focused on its activity in human bladder transitional cell carcinoma (TCC) cell lines and corresponding xenograft tumor models.[6]

• In Vitro Findings:
• Selective Gene Expression and Replication: Laboratory studies demonstrated that CG0070 selectively expressed the adenoviral E1A gene and the integrated human GM-CSF transgene in bladder cancer cell lines characterized by a defective Rb pathway. In these Rb-defective bladder TCC cells (such as RT4, SW780, UC14, and 253J B-V), the virus replicated with an efficiency comparable to that of wild-type adenovirus Ad5, producing substantial progeny virus (3,000-9,000 plaque-forming units per cell). In stark contrast, its replication was significantly attenuated (approximately 100-fold less virus production) in normal human cells possessing a functional Rb pathway, including MRC-5 fibroblasts and human aortic endothelial cells (hAEC).[10]
• Enhanced Cytotoxicity in Tumor Cells: Consistent with its selective replication, CG0070 exhibited significantly greater cytotoxicity in Rb pathway-defective bladder TCC cells. It was reported to be up to 1,000-fold more cytotoxic to these cancer cells compared to normal human cells, underscoring its tumor-specific killing ability.[10]
• In Vivo Findings:
• Antitumor Efficacy in Xenograft Models: The antitumor activity of CG0070 was demonstrated in multiple bladder cancer xenograft models. In two subcutaneous TCC xenograft models (SW780 and 253J B-V), intratumoral injections of CG0070 led to significant tumor growth inhibition compared to control (PBS) treatment. Furthermore, in a more clinically relevant orthotopic bladder TCC model (SW780-Luc cells instilled directly into the bladder of nude mice), intravesical administration of CG0070 also showed significant antitumor efficacy.[10]
• Viral Replication and Persistence in Tumors: Histological analysis using staining for adenoviral hexon protein confirmed active viral replication within the tumor mass in these animal models. In the subcutaneous models, substantial hexon staining was observed 2 days following the final virus injection (day 12 of the experiment). Importantly, viral presence, indicative of replication, was still demonstrable, although less extensive, as late as day 29 post-injection, suggesting prolonged viral persistence and activity within the tumor.[10] In the orthotopic model, viral replication was confirmed in histologic sections of explanted bladders 24 hours following intravesical virus treatment.[10]

These preclinical data provided critical proof-of-concept for CG0070's intended mechanism: selective replication in Rb-defective cancer cells, production of GM-CSF, direct oncolytic activity, and overall antitumor efficacy. These findings strongly supported its advancement into clinical trials for patients with bladder cancer.

B. Specificity for Multiple Cancers (General Statement vs. Detailed Evidence)

Background information and DrugBank entries state that CG0070 is an "oncolytic virus therapy with specificity for multiple cancers" and "has been evaluated in numerous preclinical studies".[6] The rationale for this broader specificity lies in the fact that the Retinoblastoma (Rb) pathway, which CG0070 is engineered to target, is frequently dysregulated in a wide variety of human cancers, not just bladder cancer. This theoretical basis suggests that CG0070 could potentially be effective against other Rb-deficient tumor types.

However, the detailed preclinical evidence presented within the available documentation, particularly the comprehensive study by Ramesh et al. (2006), is overwhelmingly focused on bladder cancer models.[10] While the underlying mechanism suggests broader applicability, specific preclinical data demonstrating the efficacy of CG0070 in other cancer types (e.g., lung, breast, colon) are not detailed in the provided materials. It is important to note that references to CG7870 for prostate cancer [6] pertain to a distinct oncolytic adenovirus, not CG0070.

The pronounced strategic focus by CG Oncology on bladder cancer for CG0070's development, despite the broader theoretical applicability, is noteworthy. This prioritization likely reflects a combination of factors: the strong and consistent preclinical signals observed in bladder cancer models, the significant unmet medical need in this patient population (especially for NMIBC refractory to standard therapies like BCG), and the feasibility and advantages of local intravesical delivery. Intravesical administration allows for high local concentrations of the virus at the tumor site while minimizing systemic exposure and potential side effects. Drug development is an exceptionally resource-intensive endeavor, and companies typically concentrate their efforts on indications where they possess the most robust preclinical data, a clear clinical development pathway, and a well-defined patient population with limited treatment options. Bladder cancer, particularly NMIBC, aligns well with these strategic considerations for an intravesically administered oncolytic virus like CG0070. While future exploration in other Rb-deficient cancers might be considered, the current, heavily documented clinical and preclinical strategy is centered on urologic oncology.

IV. Clinical Development in Bladder Cancer

Cretostimogene grenadenorepvec (CG0070) is the subject of a comprehensive and expanding clinical development program, predominantly focused on various stages and clinical settings of bladder cancer. The overarching goal is to establish it as a significant bladder-sparing therapeutic option.

A. Non-Muscle Invasive Bladder Cancer (NMIBC)

NMIBC represents the primary area of CG0070's clinical investigation, targeting patient populations with substantial unmet medical needs, particularly those whose disease is unresponsive to or who cannot receive standard therapies like Bacillus Calmette-Guérin (BCG).

• 1. Treatment of BCG-Unresponsive NMIBC This is a critical indication, as patients with NMIBC who fail BCG therapy have limited bladder-preserving options and often face radical cystectomy (bladder removal surgery).3 CG0070 is being developed as a novel alternative in this setting.
• BOND-003 (NCT04452591): Pivotal Phase 3 Monotherapy Trial
• Design and Population: BOND-003 is a single-arm, global Phase 3 clinical trial designed to evaluate the efficacy and safety of CG0070 as a monotherapy. The trial enrolled 112 patients with high-risk BCG-unresponsive NMIBC with Carcinoma in Situ (CIS), with or without concomitant Ta or T1 papillary tumors.[3] This patient population is considered heavily pre-treated, often having failed multiple courses of intravesical therapy.[5] The trial is fully enrolled and is ongoing in North America and the Asia-Pacific region.[5]
• Endpoints: The primary endpoint of the BOND-003 trial is the Complete Response (CR) rate at any time. A key secondary endpoint is the Duration of Response (DoR).[5] Other important outcomes include progression-free survival and cystectomy-free survival.
• Key Efficacy Results: The trial has reported compelling and durable efficacy outcomes. As of various data cutoffs in late 2024 and early 2025:
• The CR rate at any time was consistently reported between 74.5% and 75.5%.[3]
• The 12-month CR rate was approximately 46% by landmark analysis, and 50.7% by Kaplan-Meier (K-M) estimation.[3]
• The 24-month CR rate was reported as 33.7% by landmark analysis (among 101 evaluable patients), with a K-M estimated rate of 42.3%.[4]
• The median DoR had not been reached but was reported to exceed 27-28 months, indicating sustained responses.[3]
• A high percentage of patients (97.3%) remained free from progression to muscle-invasive disease at 24 months.[3]
• Furthermore, 84.5% of patients avoided radical cystectomy at 24 months, highlighting the bladder-sparing potential.[15]
• Regulatory Impact: The robust data from the BOND-003 trial were pivotal in the U.S. Food and Drug Administration (FDA) granting both Fast Track and Breakthrough Therapy Designations to CG0070 monotherapy for this indication in December 2023.[5]
• Context: BOND-003 is the cornerstone trial for CG0070's potential regulatory approval in its lead indication. The results demonstrate substantial and durable responses with monotherapy in a very challenging patient population, offering a significant potential advancement in care.
• CORE-001 (NCT04387461): Phase 2 Combination with Pembrolizumab
• Design and Population: CORE-001 was a Phase 2, single-arm, open-label clinical trial that investigated the safety and efficacy of CG0070 administered in combination with pembrolizumab, an anti-PD-1 immune checkpoint inhibitor. The trial enrolled 35 patients with high-risk BCG-unresponsive NMIBC with CIS.[13] This study was conducted in collaboration with Merck Sharp & Dohme LLC.[24]
• Endpoints: The primary endpoint was the CR rate at 12 months.[13]
• Key Efficacy Results: The combination therapy demonstrated very high rates of response:
• The CR rate at any time in the Intention-to-Treat (ITT) population was 83% (29 out of 35 patients).[13]
• The 12-month CR rate (ITT) was 57% (20/35), with a K-M estimated rate of 77.3%.[13]
• The 24-month CR rate (ITT) was 54% (19/35), with a K-M estimated rate of 69.6%.[24]
• The median DoR had not been reached but exceeded 21 months. Notably, 95% (19 out of 20) of patients who were in CR at the 12-month mark maintained their response for an additional 12 months, underscoring the durability.[24]
• Progression-Free Survival (PFS) at 24 months was 100%, with no patients progressing to MIBC or developing metastatic disease.[24]
• Cystectomy-Free Survival (CFS) at 24 months was 80% overall, and remarkably, 100% for those patients who had achieved a CR.[24]
• Regulatory Impact: Based on these promising results, the combination of cretostimogene and pembrolizumab received FDA Breakthrough Therapy Designation in May 2023.[24]
• Context: The CORE-001 trial highlights the potential synergistic activity of CG0070 when combined with systemic immune checkpoint inhibition. Such combinations may offer even higher and more durable responses by potentially overcoming different mechanisms of immune evasion in the tumor microenvironment.
• BOND II (NCT02365818 - an earlier Phase 2 study)
• The BOND II study was an earlier Phase II, single-arm, multicenter trial that assessed the safety and efficacy of intravesical CG0070 in patients with BCG-unresponsive NMIBC (including those with CIS and papillary tumors) who had refused or were unfit for cystectomy.[9]
• Interim results from this study, involving 45 patients, reported an overall 6-month CR rate of 47% for all patients. For the subset of patients with CIS (with or without Ta/T1 disease), the 6-month CR rate was 50%.[9] One patient in the study was reported to have progressed to muscle-invasive disease by the 6-month assessment.[9]
• Context: This Phase 2 study provided important early efficacy signals and safety data in the BCG-unresponsive NMIBC setting, which helped to inform the design and progression to the larger, pivotal Phase 3 BOND-003 trial.
• 2. Treatment of Intermediate-Risk NMIBC (IR-NMIBC) CG0070 is also being evaluated in patients with IR-NMIBC. This patient population typically receives adjuvant intravesical therapy to reduce the risk of tumor recurrence. The development of effective alternatives in this setting is particularly relevant given the recurrent global shortages of BCG, the standard immunotherapy for NMIBC.28
• PIVOT-006 (NCT06111235): Phase 3 Monotherapy Trial
• Design and Population: PIVOT-006 is a Phase 3, randomized, open-label, controlled clinical trial. It is designed to compare the efficacy of adjuvant cretostimogene grenadenorepvec administered after transurethral resection of bladder tumor (TURBT) versus TURBT followed by observation alone (standard of care in some settings for IR-NMIBC or when BCG is unavailable).[4] Patients randomized to the cretostimogene arm receive an induction course (weekly instillations for six weeks) followed by quarterly maintenance courses (weekly instillations for three weeks each quarter) for up to one year.[28] Patients in the observation arm who experience a recurrence may be offered treatment with cretostimogene.[28]
• Endpoints: The primary endpoint of the PIVOT-006 trial is Recurrence-Free Survival (RFS).[28] Patient-reported outcomes related to quality of life and symptoms are also being assessed.[28]
• Status: The trial is actively enrolling patients. CG Oncology announced an expected new enrollment completion date in the second half of 2025.[4] The trial officially started on December 14, 2023.[31]
• Context: PIVOT-006 aims to establish CG0070 as a treatment option for IR-NMIBC, potentially offering a new therapeutic avenue for a broader group of patients and an alternative during periods of BCG scarcity.
• NCT06253845 (NCI-2024-01394, MCC-21690): Phase 1 Trial for IR-NMIBC
• Design and Population: This is a Phase I trial designed to test the safety and effectiveness of CG0070 in treating patients with intermediate-risk NMIBC after they have undergone a transurethral resection (TURBT).[8]
• Objectives: The primary objective is to evaluate the safety of cretostimogene grenadenorepvec in this patient population. Secondary objectives include evaluating the complete response of IR-NMIBC marker lesions at 12 weeks, and assessing 12- and 24-month recurrence-free survival, progression-free survival (PFS), and cystectomy-free survival (CFS).[32]
• Treatment Outline: Patients receive CG0070 intravesically (1-hour dwell time) once weekly for 6 weeks (Induction). Patients who do not achieve a CR at 12 weeks but still have persistent disease may receive an additional 6-week induction course. Maintenance therapy involves CG0070 intravesically once weekly for 3 weeks, repeated every 3 months until 12 months from the start of the most recent induction, provided there is no disease progression or unacceptable toxicity.[32]
• Status: The trial is currently recruiting participants.[8]
• Context: This Phase 1 study will provide initial safety and efficacy data for CG0070 specifically in the IR-NMIBC population post-TURBT, complementing the larger PIVOT-006 trial.
• 3. High-Risk NMIBC (Broader Population, including BCG-Naïve/Exposed) Beyond the strictly BCG-unresponsive setting, CG0070 is being explored in broader high-risk NMIBC populations, including those who are BCG-naïve or have been exposed to BCG but may not fit the "unresponsive" criteria.
• CORE-008 (NCT06567743): Phase 2 Multi-Arm, Multi-Cohort Study
• Design and Population: CORE-008 is a Phase 2, multi-arm, multi-cohort, open-label trial designed to further evaluate the safety and efficacy of intravesical cretostimogene grenadenorepvec in various participants with high-risk NMIBC.[4]
• Cohort A (BCG-naïve): Enrolls patients with CIS +/- high-grade Ta/T1 disease who have not received prior BCG therapy.[16]
• Cohort B (BCG-exposed): Includes patients with CIS +/- high-grade Ta/T1 or papillary-only disease who have received prior BCG and recurred, either immediately after induction (BCG-resistant) or at a later point after adequate or inadequate BCG.[20]
• Cohort CX (Combination with Gemcitabine): Initiated in April 2025, this cohort evaluates the combination of cretostimogene and gemcitabine (concurrently or sequentially) in patients with HR BCG-exposed NMIBC (including CIS +/- Ta/T1 and papillary-only Ta/T1 disease).[4]
• Treatment Regimen: Intravesical cretostimogene is instilled in combination with n-dodecyl-β-D-maltoside (DDM), an excipient that enhances adenoviral delivery. The regimen consists of six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through month 12, then every six months through month 36. Re-induction is permitted.[16]
• Endpoints: The primary endpoint for populations with CIS is Complete Response (CR) at any time. For papillary-only participants, the primary endpoint is High-Grade Event-Free Survival (HG-EFS).[16] Secondary endpoints include DoR, overall EFS, bladder cancer-specific survival, RC-Free Survival, and safety.[33]
• Status: Cohorts A and B are active, with Cohort B receiving collaborative support from the Society of Urologic Oncology-Clinical Trials Consortium. Cohort CX was recently initiated.[4]
• Context: The CORE-008 trial significantly broadens the investigation of cretostimogene, aiming to define its utility in earlier lines of therapy for high-risk NMIBC (BCG-naïve) and in various BCG-exposed scenarios, as well as exploring new combination strategies (with gemcitabine). This reflects a strategy to establish cretostimogene as a versatile "backbone therapy" in NMIBC.

The development of CG0070 in NMIBC, particularly in IR-NMIBC and BCG-naïve HR-NMIBC, directly addresses the challenges posed by recurrent BCG shortages. These shortages have often led to rationing of BCG, prioritizing its use for the highest-risk patients and creating an urgent need for effective alternatives for other NMIBC patient groups.[16] Trials like PIVOT-006 and CORE-008 are designed to evaluate CG0070 as such an alternative.

B. Muscle Invasive Bladder Cancer (MIBC)

While the primary focus of CG0070 development is NMIBC, its potential is also being explored in the more advanced setting of Muscle Invasive Bladder Cancer (MIBC).

• NCT04610671 (MCC-20575, NCI-2020-09845): Phase 1b Neoadjuvant Trial
• Design and Population: This is a Phase 1b trial evaluating the safety and efficacy of neoadjuvant (pre-surgical) therapy with intravesical CG0070 in combination with intravenous nivolumab (an anti-PD-1 checkpoint inhibitor) for patients with MIBC (clinical stage cT2-4a, N$\leq$1) who are ineligible for cisplatin-based chemotherapy.[11] Cisplatin ineligibility is a common challenge in this patient population, often due to comorbidities like renal impairment.
• Treatment Regimen: Patients received six weekly intravesical instillations of CG0070 (1×1012 viral particles) and two doses of nivolumab at weeks 2 and 6, followed by radical cystectomy (RC).[11]
• Objectives: The primary objective was to assess the safety of the combination therapy. Secondary objectives included assessing pathologic response (PaR), defined as pT0N0 (no cancer found at cystectomy), and 1-year event-free survival (EFS). Exploratory objectives included correlating PaR with baseline biomarkers like E2F expression, immune infiltration, PD-L1 expression, and Tertiary Lymphoid Structure (TLS) expression.[11]
• Key Results (as of Feb 2023, 21 patients enrolled):
• Safety: The combination was generally well-tolerated. The overall rate of $\geq$grade 3 adverse events (AEs) was 60% (12/20 evaluable patients), with the vast majority (83%) related to the radical cystectomy procedure itself rather than the neoadjuvant therapy. Immune-related AEs were seen in one patient (grade 2 autoimmune thyroiditis). Importantly, there was no delay in time to RC and no unexpected surgical complications attributed to the treatment.[11]
• Efficacy: Pathologic response (pT0N0) was observed in 8 out of 15 (53%) evaluable patients who underwent RC. An additional patient had a negative post-treatment biopsy but refused RC. The overall response rate (including the pT0N0 and the biopsy-negative patient) was reported as 50%.[11]
• Exploratory Findings: Treatment response correlated with increased maturation of tertiary lymphoid structures and immunogenicity to bespoke tumor neoantigens.[11] Results of this study were published in Nature Medicine.[20]
• Status: The trial was reported as recruiting.[34]
• Context: This trial provides early evidence that CG0070, in combination with an immune checkpoint inhibitor, can induce significant pathologic responses in cisplatin-ineligible MIBC patients prior to surgery. Such neoadjuvant approaches aim to improve outcomes by downstaging tumors and potentially eradicating micrometastatic disease.

The evolution of clinical trial endpoints and patient populations for CG0070 reflects a maturing development program. Initial studies focused on safety and preliminary efficacy (CR rates) in heavily pretreated, late-stage NMIBC (BCG-unresponsive). As the program has advanced, trials are now assessing more definitive endpoints like Duration of Response (DoR), Recurrence-Free Survival (RFS), and Progression-Free Survival (PFS) in broader NMIBC populations (e.g., IR-NMIBC, BCG-naïve HR-NMIBC) and also exploring its utility in MIBC. This progression is typical as a drug candidate demonstrates promise and its potential roles become better defined.

C. General Clinical Trial Information for NMIBC

In addition to the specific trials detailed above:

• A Phase 1 trial (NCT06253845) is actively recruiting for the treatment of IR-NMIBC.[8]
• An Expanded Access Program (NCT06443944) is available for patients with NMIBC unresponsive to BCG, providing access to Cretostimogene Grenadenorepvec outside of formal clinical trials for eligible patients.[36] This program is also listed for Urothelial Carcinoma.[37]

V. Pharmacokinetics and Administration

A. Formulation and Administration Route

Cretostimogene Grenadenorepvec (CG0070) is formulated as a solid product.6 The primary route of administration in its clinical development for bladder cancer is direct intravesical instillation into the bladder via a catheter.3 This local delivery method is advantageous as it allows for high concentrations of the oncolytic virus to be delivered directly to the tumor site within the bladder lining, while potentially minimizing systemic exposure and associated side effects.

B. Excipient for Enhanced Delivery

In several clinical trials, including the Expanded Access Program (NCT06443944) and the CORE-008 study, Cretostimogene Grenadenorepvec is administered in combination with n-dodecyl-β-D-maltoside (DDM). DDM is an excipient included in the formulation to enhance adenoviral delivery into the target cells.12 This may improve the efficiency of viral infection and subsequent oncolysis.

C. Pharmacokinetic Profile

Detailed pharmacokinetic parameters such as absorption, volume of distribution, protein binding, metabolism, route of elimination, half-life, and clearance are listed as "Not Available" in the DrugBank entry for CG0070.6 This is not uncommon for investigational agents, particularly biologics like oncolytic viruses where traditional small molecule PK parameters are less relevant or more complex to define.

However, important translational data regarding the local and systemic behavior of cretostimogene were presented at the European Association of Urology (EAU) Congress in 2025. These findings indicated that following intravesical instillation, the levels of cretostimogene peaked immediately within the bladder and were sustained locally for a period of 4-5 days. Crucially, there was no evidence of systemic exposure; cretostimogene levels in systemic circulation remained below the limit of detection.[3]

These translational pharmacokinetic data are highly significant. The localized presence and persistence of the virus within the bladder support the intravesical dosing schedules used in clinical trials. The lack of systemic exposure is a key safety feature, suggesting a reduced risk of systemic adverse events commonly associated with systemically administered therapies. Furthermore, this localized activity and lack of systemic viral shedding provide evidence that special post-treatment close contact precautions for patients (to prevent viral transmission) are likely not necessary, which can improve patient convenience and quality of life.[3] The intravesical delivery also appears to reduce anti-drug antibody neutralization, thereby preserving therapeutic efficacy.[3]

VI. Safety and Tolerability

Across multiple clinical trials, Cretostimogene Grenadenorepvec (CG0070) has generally demonstrated a favorable and manageable safety profile, particularly when administered as a monotherapy via intravesical instillation.

A. Monotherapy in NMIBC (BOND-003 and earlier studies)

In the pivotal Phase 3 BOND-003 trial evaluating CG0070 monotherapy in high-risk BCG-unresponsive NMIBC, the treatment was reported to be very well-tolerated.3

• No Grade 3 or greater treatment-related adverse events (TRAEs) were reported, and there were no deaths attributed to the treatment.[3]
• No patients discontinued cretostimogene due to treatment-related side effects.[3]
• The most common TRAEs (occurring in $\geq$10% of patients) were generally localized to the genitourinary system and transient in nature. These included bladder spasm, pollakiuria (increased frequency of urination), micturition urgency, dysuria (painful urination), and hematuria (blood in urine).[3]
• The median time to resolution for TRAEs of any grade was reported to be only one day, indicating their typically short-lived nature.[3]
• Patient adherence to the treatment regimen was high, with 97.3% of patients completing all expected treatments, demonstrating favorable patient compliance and tolerability.[3]

Earlier Phase II studies, such as BOND II, also reported a tolerable safety profile, with the most common adverse events being urinary bladder spasms (36%), hematuria (28%), dysuria (25%), and urgency (22%).[9] A retrospective review of 15 patients treated with CG0070 also noted hematuria (33.3%), malaise/fatigue (33.3%), and urgency/frequency (26.7%) as common side effects, with 40% of patients experiencing no adverse events.[27]

B. Combination Therapy

• CORE-001 (CG0070 + Pembrolizumab in NMIBC): In this Phase 2 trial, treatment-related adverse events were generally limited to transient Grade 1-2 local-regional genitourinary events. There were no reports of Grade 3 or 4 TRAEs, or serious adverse events (SAEs) attributed to the combination treatment of CG0070 and pembrolizumab.[13]
• NCT04610671 (CG0070 + Nivolumab in MIBC): In this Phase 1b neoadjuvant study for cisplatin-ineligible MIBC, the overall rate of Grade 3 or higher AEs was 12 out of 20 patients (60%). However, the vast majority of these (83%) were related to the subsequent radical cystectomy procedure rather than the investigational drug combination. One patient experienced a Grade 2 immune-related AE (autoimmune thyroiditis). Importantly, the neoadjuvant treatment did not lead to delays in the time to radical cystectomy and there were no unexpected surgical complications arising from the treatment.[11]

The consistent reports of a manageable safety profile, especially the low incidence of severe TRAEs with monotherapy and the predominantly local nature of side effects, are crucial for a therapy intended for intravesical administration, often in an outpatient setting. This favorable tolerability, combined with the lack of systemic viral exposure, supports its potential as a bladder-sparing option that can be administered with a familiar urological workflow.

VII. Regulatory Status and Designations

Cretostimogene Grenadenorepvec (CG0070) has achieved significant regulatory milestones from the U.S. Food and Drug Administration (FDA), reflecting its potential to address unmet medical needs in bladder cancer.

A. FDA Fast Track Designation

• Cretostimogene grenadenorepvec monotherapy received FDA Fast Track Designation in December 2023. This designation is for the treatment of patients with high-risk BCG-unresponsive NMIBC with CIS, with or without concomitant Ta or T1 papillary tumors.[5] (Some secondary reports mention January 2024 [15], but primary company communications point to December 2023). Fast Track designation is intended to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need.

B. FDA Breakthrough Therapy Designation

Cretostimogene grenadenorepvec has received FDA Breakthrough Therapy Designation for two distinct applications:

• Monotherapy: Granted in December 2023 for cretostimogene grenadenorepvec as a monotherapy for the treatment of patients with high-risk BCG-unresponsive NMIBC with CIS (with or without Ta/T1 tumors).[5] (Again, some secondary reports cite January 2024 [15]).
• Combination Therapy: Granted in May 2023 for cretostimogene grenadenorepvec in combination with pembrolizumab for the treatment of patients with BCG-unresponsive, high-risk NMIBC with CIS.[24] Breakthrough Therapy Designation is designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). The granting of these designations for both monotherapy and combination therapy underscores the promising clinical data generated by CG0070.

C. Expanded Access Program (EAP) (NCT06443944)

CG Oncology has initiated an Expanded Access Program (EAP) for cretostimogene grenadenorepvec in the United States.

• Purpose: The EAP (ClinicalTrials.gov Identifier: NCT06443944) is an open-label, compassionate use clinical trial designed to provide access to cretostimogene for a diverse population of real-world patients with BCG-unresponsive NMIBC with CIS. This program is for patients who may not otherwise be eligible for currently enrolling formal clinical trials.[1]
• Eligibility Criteria: Key eligibility criteria include age $\geq$18 years, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3, and pathologically confirmed BCG-unresponsive CIS (with or without high-grade Ta/T1 disease) after completion of adequate BCG treatment, as defined by the US FDA.[12]
• Treatment Regimen: Patients in the EAP receive intravesical cretostimogene in combination with the excipient n-dodecyl-β-D-maltoside (DDM). The treatment schedule involves six weekly doses during an induction phase, followed by three weekly maintenance cycles administered quarterly through Month 12, and then maintenance cycles every six months through Month 24. Re-induction with another course of cretostimogene is permitted if needed.[12]
• Objectives: The primary objective of the EAP is to evaluate the safety of cretostimogene in this real-world setting. Secondary outcome measures include Complete Response (CR) at any time and at 12 months, Duration of Response (DoR), high-grade Recurrence-Free Survival (RFS), Progression-Free Survival (PFS), and Radical Cystectomy-Free Survival.[12] Exploratory outcomes include health-related quality of life, overall survival, and biomarker assessments.
• Implementation: The program aims to include a broad cross-section of geographically and socioeconomically diverse clinical sites and is actively recruiting.[12]

D. European Medicines Agency (EMA) Status

The provided research materials do not contain specific information regarding any submissions made to, or opinions issued by, the European Medicines Agency (EMA) concerning Cretostimogene Grenadenorepvec (CG0070).2 While one document discusses an EMA review for a different bladder cancer therapy (nogapendekin alfa inbakicept) 39, there is no corresponding information for CG0070. Therefore, its regulatory status with the EMA is not detailed in the available sources.

VIII. Developer Information: CG Oncology

A. Overview

CG Oncology, Inc. (NASDAQ: CGON) is a late-stage clinical biopharmaceutical company. Its primary mission is the development and commercialization of cretostimogene grenadenorepvec, positioning it as a potential cornerstone, bladder-sparing therapeutic for patients afflicted with bladder cancer.1 The company's vision is to provide innovative immunotherapies that enable urologic cancer patients to live with dignity and an enhanced quality of life.3

B. Founding and Leadership

CG Oncology, Inc. was founded on September 24, 2010, by Alex Yeung and Paul A. DeRidder, MD. The company was formerly known as Cold Genesys, Inc..40 It is headquartered in Irvine, California, USA. As of 2024-2025, the company is led by Arthur Kuan, who serves as Chairman of the Board and Chief Executive Officer.4 Other key executives include Ambaw Bellete (President and Chief Operating Officer), Dr. Vijay Kasturi, M.D. (Chief Medical Officer), and Corleen M. Roche (Chief Financial Officer).4

C. Development Pipeline Focus

CG Oncology has established a robust and focused clinical trials program centered on cretostimogene grenadenorepvec for NMIBC. This program encompasses studies evaluating the drug as a monotherapy and in combination with other agents, across various NMIBC risk strata. Key areas of investigation include high-risk BCG-unresponsive NMIBC, intermediate-risk NMIBC, and high-risk NMIBC in both BCG-naïve and BCG-exposed patients.1 The flagship clinical trials in their pipeline include BOND-003 (Phase 3, monotherapy, BCG-unresponsive HR-NMIBC), PIVOT-006 (Phase 3, monotherapy, IR-NMIBC), CORE-001 (Phase 2, combination with pembrolizumab, BCG-unresponsive HR-NMIBC), and CORE-008 (Phase 2, multi-cohort including BCG-naïve HR-NMIBC and combinations).1

D. Financials and Recent Milestones

CG Oncology has actively reported its financial results and corporate updates, including those for the first quarter of 2025 and the full year 2024.4

Recent significant milestones include:

• A successful follow-on public equity offering that raised approximately $238 million in gross proceeds. This financing is expected to extend the company's operational runway into the first half of 2028, supporting ongoing clinical development programs and commercial readiness activities.[20]
• Presentation of updated positive clinical data from the BOND-003 trial (Cohort C and Cohort P) at major urological conferences such as the American Urological Association (AUA) Annual Meeting and the European Association of Urology (EAU) Congress in 2025.[4] These presentations highlighted best-in-class durability and tolerability.
• Initiation and expansion of the CORE-008 clinical trial, including cohorts for BCG-naïve patients (Cohort A), BCG-exposed patients (Cohort B), and a combination with gemcitabine (Cohort CX).[4]
• Publication in the prestigious journal Nature Medicine of the final results from the Phase 1b study evaluating cretostimogene in combination with nivolumab as neoadjuvant therapy for muscle-invasive bladder cancer.[20] Similarly, final results from the CORE-001 Phase 2 trial (cretostimogene plus pembrolizumab in BCG-unresponsive NMIBC) were published in Nature Medicine and presented at the ASCO 2024 meeting.[25]
• The company listed on the NASDAQ stock exchange under the ticker CGON on January 25, 2024.[41]

These milestones reflect a period of significant clinical and corporate progress for CG Oncology as it advances cretostimogene grenadenorepvec towards potential market approval.

IX. Summary and Future Outlook

Cretostimogene grenadenorepvec (CG0070) has emerged as a highly promising investigational oncolytic immunotherapy for bladder cancer, particularly for Non-Muscle Invasive Bladder Cancer (NMIBC). Its dual mechanism of action, involving selective tumor cell lysis via Rb-pathway targeting and robust immune stimulation through GM-CSF expression, offers a multifaceted approach to cancer treatment. This mechanism is designed not only for direct tumor destruction but also for the induction of a durable, systemic anti-tumor immune response, potentially leading to long-term disease control.

Clinical development has yielded compelling results, especially in the challenging setting of high-risk BCG-unresponsive NMIBC. The pivotal Phase 3 BOND-003 monotherapy trial has demonstrated high complete response rates (approximately 75% at any time) and impressive durability of response (median DoR exceeding 28 months and ongoing, with a 24-month K-M estimated CR rate of 42.3%). Furthermore, combination therapy with the checkpoint inhibitor pembrolizumab in the Phase 2 CORE-001 trial showed even higher response rates (83% CR at any time, 54% CR at 24 months ITT) and excellent durability. These efficacy data are coupled with a generally favorable safety and tolerability profile, characterized primarily by transient, local genitourinary adverse events, and minimal systemic toxicity due to its intravesical administration route. The lack of systemic viral exposure further enhances its safety profile and patient convenience.

The FDA has recognized the potential of cretostimogene grenadenorepvec by granting it Fast Track and Breakthrough Therapy Designations for both monotherapy and combination with pembrolizumab in specific BCG-unresponsive NMIBC indications. An Expanded Access Program is also in place, providing the therapy to eligible patients outside of formal trials.

CG Oncology is strategically positioning cretostimogene grenadenorepvec as a "potential backbone bladder-sparing therapeutic." This is evidenced by its investigation as monotherapy across different NMIBC risk strata (BOND-003 for BCG-unresponsive high-risk; PIVOT-006 for intermediate-risk) and in various combination regimens (CORE-001 with pembrolizumab; CORE-008 exploring combinations including with gemcitabine, and in BCG-naïve high-risk populations). This comprehensive approach aims to address unmet needs across the NMIBC spectrum, including scenarios impacted by BCG shortages. Early investigations in neoadjuvant MIBC also suggest broader potential in urologic oncology.

The future outlook for cretostimogene grenadenorepvec appears promising. Successful completion and positive outcomes from ongoing and planned pivotal trials, particularly BOND-003 and PIVOT-006, will be crucial for securing regulatory approvals. Further data from combination studies within the CORE-008 program will help define its role alongside other therapies. If approved, cretostimogene grenadenorepvec has the potential to significantly alter the treatment landscape for NMIBC, offering a much-needed, effective, and well-tolerated bladder-sparing option for patients, potentially reducing the reliance on radical cystectomy and improving quality of life. Its unique mechanism, strong clinical data to date, and focused development strategy position it as a leading candidate in the field of oncolytic virotherapy for bladder cancer.

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