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Mark D. Tyson, II: Good morning. My name is Mark Tyson, and I'm delighted to present the pivotal results of BOND-003, a single-arm, open-label, phase III registration study evaluating cretostimogene grenadenorepvec monotherapy for BCG-unresponsive non-muscle-invasive bladder cancer. I have no conflicts of interest with CG Oncology.

So, what is cretostimogene? Creto is a conditionally replicating oncolytic serotype 5 adenovirus that's been designed to preferentially replicate in and kill cancer cells. The E2F-1 promoter drives the expression of essential viral genes while restricting replication to RB-pathway-deficient tumor cells, thereby sparing normal tissue. Creto also encodes the complementary DNA for GM-CSF, which is a potent cytokine inducer of antitumor immunity in animal models. The primary receptor for Creto is the Coxsackie Adenovirus Receptor, which is expressed in all stages of bladder cancer.

After Creto binds to the CAR receptor, it enters malignant cells where viral replication leads to tumor cell lysis and the release of viral and tumor-specific antigens. These antigens are picked up by dendritic cells and presented to T cells, which initiate the local antitumor immune response, thereby potentiating the immunotherapy effect.

This leads us to BOND-003 cohort C, a phase III study evaluating Creto in patients with BCG-unresponsive CIS according to the strict definition laid out by the FDA in their 2018 guidance. Concomitant papillary disease was allowed, but it had to be completely resected prior to the initiation of treatment. Importantly, patients underwent mandatory biopsies at 12 months, which included five regions of the bladder as well as the prostatic urethra. Patients underwent six sequential weekly installations of Creto followed by a repeat induction for non-responders or maintenance for responders. The primary endpoint was the complete response rate at any time point. Key secondary endpoints included duration of response as well as recurrence-free, progression-free, and cystectomy-free survival. In total, 112 patients enrolled in BOND-003, and the data presented here are up to a cutoff date of April 1, 2024.

In terms of baseline characteristics, most patients were white males of Medicare age, 18% did have concomitant papillary disease, and, as expected, the cohort was heavily pretreated with the median number of prior BCG installations being 12, with several other patients also having received pembrolizumab.

In terms of the efficacy analysis, the complete response rate at any time point for all patients based on central pathology review was 75.2% with a confidence interval indicating a range of plausible CRs between 65% and 83%. The swimmer's plot is shown here, and a key observation worth noting is that 54% of patients who did not respond to the initial induction course of Creto went on to respond to the second induction course of Creto, with several of those patients having a durable response beyond 12 months. This speaks to the oncolytic immunotherapy mechanism of action, where the immune system switches from innate to adaptive, as we see with a second induction course of BCG. Secondly, of the 35 patients who hit the twelve-month time point, 29 of them, or 83%, maintained a duration of response greater than 12 months, with 22 complete responders still pending. Lastly, 92% of patients had not undergone a radical cystectomy by the 1-year time point.

In terms of tolerability, cretostimogene has been generally well tolerated. There were no grade 3 treatment-related adverse events and no deaths. There were 2 grade 2 serious adverse events and 1 patient who discontinued the trial, but this was due to an unrelated adverse event. 94.5% of patients completed all the expected treatments.

With respect to the instillation process itself, Creto administration is a familiar and convenient workflow. It can be instilled by nurses or medical assistants, and its favorable tolerability profile lends itself to high patient compliance. This is supported by the observation that no patient was unable to tolerate the instillation and dwell.

Recognizing that cross-study comparisons are difficult due to differences in the underlying populations, Creto would at least appear to compare favorably to the current non-surgical co-standards of care. A 75% complete response rate observed for Creto monotherapy compares favorably to the 62% observed for 803 combination therapy with BCG, to the 51% observed for nadofaragene, and to the 41% observed for pembrolizumab. Similarly, the duration of complete response for Creto monotherapy compares favorably with 83% of responders at the 12-month time point, having a duration of response greater than 12 months, versus the 58% for 803, and the 46% both for nadofaragene and pembrolizumab, respectively. Toxicity also compares favorably, with BOND-003 observing no grade 3 treatment-related adverse events.

Based upon the strength of these data, the FDA has granted CG Oncology Fast Track & Breakthrough Therapy designation for cretostimogene and its development in the treatment of BCG-unresponsive non-muscle-invasive bladder cancer. Two important amendments have recently been implemented. The first is for complete responders who have made it to the end of the protocol. They can now continue in years 2 and 3 on Q6 month dosing of maintenance therapy, and we've also added cohort P, a papillary-only cohort of patients with BCG unresponsive papillary-only non-muscle invasive bladder cancer, and we will speak more about the design and implementation of cohort P in the learning lab on Sunday at the AUA.

I'd also like to take this opportunity to announce cretostimogene's Expanded Access and Compassionate Use Program. The program has simplified inclusion and exclusion criteria, and it's specifically designed to incorporate a geographically and ethnically diverse population, offering real-world data insights into safety, efficacy, and patient-reported outcomes.

There is an important collaboration worth highlighting as well between the SUO-CTC and CG Oncology. The first is PIVOT-006, led by Dr. Rob Svatek. This is a phase three study comparing cretostimogene to TURBT alone for patients with BCG-naive intermediate-risk, non-muscle invasive bladder cancer, as well as CORE-008 on the horizon, a phase II, multi-arm, multi-cohort study involving cretostimogene for high-risk BCG-naive and BCG-exposed, non-muscle invasive bladder cancer.

I'd like to take this opportunity to thank the patients and their families, the study coordinators, and the nurses, as well as the key collaborators listed here, but especially Dr. Roger Li and Ed Uchio, who were instrumental in the success of this trial. Thank you.