Unique Mechanism of Action

Cretostimogene is an investigational engineered, conditionally replicating oncolytic immunotherapy that has been designed to preferentially replicate in retinoblastoma (Rb) gene pathway-defective cells present in the majority of urothelial carcinomas and trigger an anti-tumor immune response. Cretostimogene enters the tumor by binding to Coxsackievirus and Adenovirus Receptors (CAR) present in specialized intracellular junctions and tight junctions of polarized epithelial cells.

Mechanism of action of Cretostimogene grenadenorepvec.
This video has been sponsored by CG Oncology.

There are two modifications made to cretostimogene for tumor selectivity and potency. The first modification is the insertion of an E2F-1 promoter in cretostimogene which acts as a safety mechanism to selectively replicate and lyse Rb-defective tumor cells rather than healthy cells which have intact Rb pathways. The second modification is the insertion of the gene for the cytokine granulocyte-macrophage colony stimulation factor (GM-CSF). GM-CSF is widely recognized as a potent stimulator of longer-term anti-tumor activity and we believe its addition to the viral construct may both prime the immune system and induce tumor-specific immunity. Replication and lysis of Rb-defective tumor cells by cretostimogene may trigger an immunogenic cell death that stimulates an anti-tumor immune response.

Targeted Dual Mechanism of Action of Cretostimogene Grenadenorepvec

Cretostimogene grenadenorepvac is an Oncolytic immunotherapy (OIT) that selectively replicates within cells with an impaired retinoblastoma pathway. Additionally, release of tumor antigens and GM-CSF stimulate a systemic immune response for a potential anti-tumor effect. Cretostimogene grenadenorepvec was designed to work in two important and complementary ways. First, it replicates inside the tumor’s cells causing tumor cell lysis and immunogenic cell death. Then, the rupture of the cancer cells can release tumor-derived antigens, along with GM-CSF, that can stimulate a systemic anti-tumor immune response that involves the body’s immune system

Unmet Need in Bladder Cancer

people will be diagnosed with Bladder Cancer this year1

Non-muscle invasive bladder
cancer (NMIBC) represents

%

of newly diagnosed bladder cancer cases2

%

of high-risk patients will recur within 1 year3

Up to

%

of patients either do not respond or eventually develop disease recurrence after first-line BCG therapy3

Bladder cancer is the 7th most common form of cancer in the US, men account for three-quarters of newly diagnosed cases. Bladder cancer patients are generally from high-risk populations, with 74% of patients over 65 years old and a median age of 731 years old.

NMIBC accounts for approximately 75% of newly diagnosed patients, and includes three stages: CIS-containing tumors, Ta and T1. T2 through T4 stage make up MIBC and are indicative of more aggressive locally advanced and metastatic disease. Bladder cancer has metastasized in an estimated 5% of patients with newly diagnosed disease.2

Bladder cancer is a highly recurrent disease3,4 and the global bladder cancer treatment market has been forecasted to be approximately $9.9 billion by 2028, according to Evaluate Pharma.5

Risk Stratification and Staging of Bladder Cancer:

Risk Stratification of Bladder Cancer2
NMIBC graphic image
This video has been sponsored by CG Oncology.

Risk Stratification and staging of bladder cancer:

Gary Steinberg, MD, Professor Department of Urology, RUSH medical College explains how risk stratification has helped in the management of NMIBC.

Transcript:
The risk stratification for non-muscle invasive bladder cancer has really helped the patients as well as the clinicians. Non-muscle invasive bladder cancer has two major concerns. One is that the bladder cancer comes back, what we call recurrence, and that the bladder cancer can progress to potentially even muscle invasive or higher-grade cancers.

What are the different risk stratification levels in NMIBC?

Gary Steinberg, MD, Professor Department of Urology, RUSH medical College explains how risk stratification has helped in the management of NMIBC.

Transcript:
How do we define the different risk stratification levels in the American Urology Association, the Society of Urologic Oncology, low risk is a small, papillary, non-invasive, lowgrade bladder tumor. It’s a first-time event less than three centimeters in size. The intermediate risk is, typically, the low-risk patients, or the low-grade patients, papillary, non-invasive who have recurred, or they can have multiple low grade papillary tumors, or they can have a large, low grade papillary tumor. In general, they’re all mostly low grade. Now, in the American Urology Association risk stratification, we also include high grade papillary tumors, first time event, less than three centimeters. In general, it’s a solitary tumor, but we can have two to three tumors and still be in the intermediate risk category, especially if they’re small. Anytime a high-grade intermediate risk tumor recurs, they then automatically are in the high-risk category. The highrisk category is essentially anybody with high grade disease, T1, high grade carcinoma in situ, or Ta high grade greater than three centimeters, or recurrent Ta high grade.

This video has been sponsored by CG Oncology.

Non-muscle Invasive Bladder Cancer (NMIBC):

This video has been sponsored by CG Oncology.

Impact of the BCG shortage: Ashish M. Kamat, M.D. MBBS. Endowed Professor of Urologic Oncology (Surgery) and Cancer Research at University of Texas MD Anderson Cancer Center discusses the history and impact of the BCG shortage in the US and life-altering impact on patients.

Transcript:
The BCG shortage has been going on for quite some time, and over the years we have had the fortune, or I guess the misfortune in many ways to find the impact of the BCG shortage on patients. Transcript: The BCG shortage has been going on for quite some time, and over the years we have had the fortune, or I guess the misfortune in many ways to find the impact of the BCG shortage on patients.

Patients with high-grade NMIBC are treated with surgical removal of their lesions and intravesical treatment with BCG3,4. However, there is shortage of BCG, and it is currently not available to Intermediate-Risk patients or to all patients with High-Risk disease. There is a great need for a local, well-tolerated, and effective bladder preserving option for patients with intermediate risk as well as high risk BCG-unresponsive NMIBC. Despite BCG’s effectiveness with nearly 70% of patients experiencing a Complete Response after an initial induction course of therapy, approximately 50% of these patients will experience a recurrence and few treatment options are available for patients who become unresponsive to BCG treatment.

FDA approved new therapeutic options in January 2020 and December 2022, but they are not widely available. This leaves most patients with their only treatment option being bladder removal (cystectomy). Cystectomy is associated with negative outcomes, mortality, and a reduced quality of life6,7,8,9. Patients report preferring bladder preservation, and in many cases due to co-morbid conditions, are not eligible for such a demanding surgery2.

This video has been sponsored by CG Oncology.

Definition of BCG shortage: Ashish M. Kamat, M.D. MBBS. Endowed Professor of Urologic Oncology (Surgery) and Cancer Research at University of Texas MD Anderson Cancer Center explains how the definition of BCG unresponsive disease came about and its impact clinical studies for patients with NMIBC.

Transcript:
The definition of BCG unresponsive disease has undergone changes over many years, and it actually started at an AUA meeting many years ago, and then was modified and ratified by the AUA group, the GU ASCO Group led by Seth Lerner, the International Bladder Cancer Group, which I happen to lead, and it was ultimately adopted by the FDA as an amalgamation of all these recommendations. And why was this important? Well, it was important because prior to the actual definition of BCG unresponsiveness being formalized, a lot of investigators, a lot of pharmaceutical companies invested a lot of time and effort. And of course, patients invested a lot of time and effort doing clinical studies after BCG had not worked. But we couldn’t really make head or tail out of the results of those studies because there was no uniformity in the inclusion criteria, the patient selected the endpoints. And that’s why when the definition of BCG unresponsive disease was adopted and formalized in the FDA guidance document 2018, there was an explosion of clinical studies. And these studies now follow that paradigm for regulatory and approval processes.

Experts explain the patient journey:

This video has been sponsored by CG Oncology.

Bladder Cancer Facts:

Sima P. Porten MD, MPH Associate Professor in Residence, UCSF, explains the incidence and risk factors for bladder cancer.

Transcript:
Bladder cancer is often under-recognized and underdiagnosed. However, it is a common cancer among patients in the United States. It affects men more than women, and approximately 80,000 cases in 2022 with about 18,000 deaths. Some known exposures such as cigarette smoking, carcinogens in the environment, carcinogens in drinking water such as arsenic have been described as being a contributor to development of bladder cancer. Most patients who present with bladder cancer present with non-muscle invasive disease about 70%, and about 20% present with muscle invasive disease and approximately five to 10% present with widespread disease or metastatic disease.

Patient Journey:

Siamek Daneshmand MD, Professor of Urology (Clinical Scholar), Director of Clinical Research, USC Keck School of Medicine of USC, explains the patient journey for patients with NMIBC and the intense follow-up patients face.

Transcript:
So patients with non-muscle invasive bladder cancer typically have a lot of treatments, intravesical treatment, typically BCG that’s been around for a long time, and they undergo surveillance cystoscopies afterwards looking for recurrence. The recurrence rates can be very high, 50 to 70% depending on the grade and the stage of the disease initially. But more importantly, we want to prevent the progression of disease which can happen in 20 to 30% of cases. So, there’s a lot of surveillance cystoscopies that happen after treatment, and these are every three to four months, typically in the office. A lot of biopsies, going back to the operating room to reassess the bladder, making sure that we don’t have recurrences or trying to catch those recurrences early on in the game.

This video has been sponsored by CG Oncology.

Cretostimogene grenadenorepvec and clinical trials in NMIBC:

Cretostimogene grenadenorepvec is being investigated in a global Phase 3 trial (BOND-003) as a monotherapy for the treatment of BCG-unresponsive, Non-Muscle Invasive Bladder Cancer (NMIBC). Most patients with high-risk NMIBC (CIS with or without Ta/T1, Ta or T1) who do not respond to BCG intravesical therapy (standard of care). For information on BOND-003 study, click here.

In this video, Mark D. Tyson, MD, MPH, highlights the background and notable findings from the phase 3 BOND-003 trial (NCT04452591) exploring cretostimogene grenadenorepvec in patients with BCG-unresponsive non-muscle-invasive bladder cancer.

BOND-003 Phase 3 Results: Revolutionizing Bladder Cancer Treatment with Intravesical Cretostimogene Grenadenorepvec Monotherapy for High-Risk BCG-Unresponsive NMIBC – Mark Tyson

Cretostimogene Grenadenorepvec Therapy Aims to Fill an Unmet Need in the Bladder Cancer Armamentarium – Robert Svatek

Cretostimogene is also being investigated in a Phase 3 trial (PIVOT-006) as a monotherapy for the treatment of Intermediate-Risk NMIBC.

Cretostimogene grenadenorepvec is being further investigated in a clinical collaboration with Merck to evaluate the combination of cretostimogene grenadenorepvec with the anti-PD-1 therapy, pembrolizumab, in a Phase 2 clinical study (CORE-001) for the treatment of high risk, NMIBC in the BCG-unresponsive patient population.

Listen to Dr. Roger Li, MD of Genitourinary Oncology at Moffit Cancer Center talk about CORE-001.

Bladder Cancer Advocacy

This video has been sponsored by CG Oncology.

BCAN – For and by bladder cancer patients: Sima P. Porten MD, MPH, Associate Professor in Residence, UCSF discuss why the Bladder Cancer Advocacy Network (BCAN) is an important organization for patients, providers and researchers- an organization for and by bladder cancer patients that fosters collaboration.

Transcript:
BCAN or the Bladder Cancer Advocacy Network was founded in 2005 and is one of the only national advocacy networks, primarily driven by patients and driven for patients. It’s a really, really special organization because it really keeps the patient experience, priorities and journey through the treatment of bladder cancer at the center in everything that it does. And I’ve been very lucky to be a part of this organization. I primarily started out as a John Quale Travel fellow, and that means that I was given the opportunity to come and present my research at the scientific think tank, which is this wonderful, very special meeting where world renowned researchers from the United States and also abroad come to exchange scientific ideas in a very collaborative space with medical oncologist, urologist, basic scientist, environmental scientist, patient advocates, which is a really, really important part of the process as well as now our advanced practice providers and NPs and our community urologists as well, because they’re important partners in taking care of all of our patients.

For more information on bladder cancer go to Bladder Cancer Advocacy Network at www.BCAN.org.

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REFERENCES:

1. Key Statistics for Bladder Cancer – American Cancer Society. https://www.cancer.org/cancer/types/bladder-cancer/about/key-statistics.html Accessed March 2024.

2. Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, Pruthi R, Quale DZ, Ritch CR, Seigne JD, Skinner EC, Smith ND, McKiernan JM (2016). Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 196:1021-1029.

3. Richard J Sylvester 1, Adrian P M van der Meijden, Willem Oosterlinck, J Alfred Witjes, Christian Bouffioux, Louis Denis, Donald W W Newling, Karlheinz Kurth. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Uro. 2006 Mar;49(3):466-5; discussion 475-7. doi: 10.1016/j.eururo.2005.12.031. Epub 2006 Jan 17

4. Rouanne M, Adam J, Radulescu C, Letourneur D, Bredel D, Mouraud S, Goubet AG, Leduc M, Chen N, Tan TZ, Signolle N, Bigorgne A, Dussiot M, Tselikas L, Susini S, Danlos FX, Schneider AK, Chabanon R, Vacher S, Bièche I, Lebret T, Allory Y, Soria JC, Arpaia N, Kroemer G, Kepp O, Thiery JP, Zitvogel L, Marabelle A. BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer. J Clin Invest. 2022 Jun 15;132(12):e145666. doi: 10.1172/JCI145666. PMID: 35503263; PMCID: PMC9197524.

5.-Article – Elevate Pharma. https://www.evaluate.com/resources/ Accessed March, 2024.

6. Berger I, Xia L, Wirtalla C, Dowzicky P, Guzzo TJ, Kelz RR. 30-day readmission after radical cystectomy: Identifying targets for improvement using the phases of surgical care. Can Urol Assoc J. 2018;13(7):E190-e201.

7. Sadowski DJ, Warner H, Scaife S, McVary KT, Alanee SR. 30-day all-cause hospital readmission after cystectomy: No worse for rural Medicare residents. Urol Oncol. 2018;36(3):89.e87-89.e11.

8. Pak JS, Lee JJ, Bilal K, Finkelstein M, Palese MA. Utilization trends and short-term outcomes of robotic versus open radical cystectomy for bladder cancer. Urology. 2017;103:117-123.

9. Maiboma SL, Poulsena AM, Thind PO, Sallinga ML, Sallinga LN, Kehletb H, Brassoa K, Joensena UN, (2021). Morbidity and Days Alive and Out of Hospital Within 90 Days Following Radical Cystectomy for Bladder Cancer. European Journal of Urology 28(28) 1-8. www.sciencedirect.com.