DD From Sesen's Annual Report Disease Overview
Most cancers that form in the bladder are transitional cell carcinomas that derive from the transitional cell lining of the bladder. Transitional cell carcinoma of the bladder can be characterized as either high-grade or low-grade. Low-grade bladder cancer often occurs in the lining of the bladder, but rarely invades the muscular wall of the bladder or spreads to other parts of the body and is unlikely to be fatal. High-grade bladder cancer commonly occurs in the bladder, has a strong tendency to invade the muscular wall of the bladder, spread to other parts of the body and is more likely to result in death. Bladder cancer is also divided into muscle-invasive and non-muscle invasive, based on invasion of the muscularis propria, which is the thick muscle deep in the bladder wall. Muscle-invasive disease is more likely to spread to other parts of the body. There are three forms of high-grade NMIBC:
Ta, a papillary tumor in the innermost layer of the bladder lining;
T1, a papillary tumor that has started to grow into the connective tissue beneath the bladder lining; and
CIS, flat lesions of the transitional cell lining of the bladder.
Papillary tumors are generally low-grade with low risk of progression, although about two to nine percent are high-grade, with a moderately high risk of progression to muscle-invasive bladder cancer. Evaluable CIS tumors are always high-grade, with a worse prognosis than papillary tumors, as such CIS tumors are more aggressive, with a higher probability of progression to muscle-invasive disease. Furthermore, the incidence of CIS in conjunction with Ta or T1 tumors results in a higher risk of recurrence and progression.
About 75% to 85% of bladder cancers are non-muscle invasive. Of these, Ta tumors account for about 70%, T1 tumors account for about 20% and CIS lesions account for about 10%. According to World Cancer Research Fund International figures, bladder cancer is the tenth most common cancer diagnosed worldwide and the second most common malignancy of the genitourinary system, which refers to cancers of the urinary system of men and women and the reproductive organs of men. In 2020, there were an estimated 573,000 new cases of bladder cancer diagnosed and 213,000 deaths worldwide, according to data from the Global Cancer Observatory. The 5-year global prevalence of bladder cancer, or the number of individuals with bladder cancer in a 5-year period, is estimated at 1.7 million individuals. The most recent data from the NCI's Surveillance, Epidemiology and End-Result Program ("SEER") estimated that approximately 84,000 new cases of bladder cancer would be diagnosed in 2021 and there would be approximately 17,000 deaths due to bladder cancer in the United States during 2021.
Based on a 2014 publication in Current Opinion in Urology, among cancers in the United States, bladder cancer has the highest per-patient treatment costs, with an estimated overall cost of approximately $4.0 billion annually and has the highest overall cost among the elderly. Based on our assessment of the market, the treatment paradigm has remained the same since those figures were generated, and we believe the cost of care has increased. NMIBC makes up 75% to 85% of all bladder cancers. The high recurrence rate and ongoing invasive monitoring requirement of bladder cancers are the key contributors to the economic and human toll of this disease. Bladder cancer occurs predominantly in older patients (about nine of the ten people with bladder cancer are over the age of 55 years). The median age at diagnosis is approximately 73 years of age. Overall, the five-year survival rate for bladder cancer in the United States is 77%. While the five-year survival rates are 98% for stage zero and 88% for stage one NMIBC, once the cancer becomes invasive, the rates drop dramatically with five-year survival rates of 63%, 46% and 15% for stage two, three and four muscle invasive bladder cancers, respectively. We are targeting patients with non-muscle invasive CIS of the bladder in patients previously treated with adequate or less than adequate BCG. Our initial target market includes the approximately 6,000 patients in the US diagnosed annually, including those patients with non-muscle invasive CIS of the bladder previously treated with adequate or less than adequate BCG. We would expect that, if Vicineum for the treatment of non-muscle invasive CIS of the bladder in patients previously treated with adequate or less than adequate BCG is approved by the FDA, patients would receive treatment until the earlier of 2 years and disease recurrence.
Current Approaches to Treatment
Within non-muscle invasive CIS of the bladder in patients previously treated with adequate or less than adequate BCG, the initial treatment of Ta or T1 is transurethral resection of the bladder tumor ("TURBT") followed by BCG treatment. For CIS, whether or not TURBT is an option, BCG is the standard of care. BCG is a live attenuated strain of Mycobacterium bovis, with6 a diminished virulence in humans. Since BCG works by utilizing an immune/inflammatory mechanism, BCG is generally initiated two to four weeks after TURBT, allowing the urothelium to heal and lowering the risk of systemic infection. When high-grade bladder tumors have been completely resected, BCG is used as adjuvant therapy to prevent recurrence. In patients with residual disease after resection, BCG helps to eradicate residual disease and delay progression. The BCG regimen consists of an induction phase followed by a maintenance phase. The induction phase involves six consecutive once-weekly instillations of the drug into the bladder. The maintenance phase involves three consecutive once-weekly instillations repeated every three to six months for at least one year. The response rate to a single induction phase of BCG is 60% to 70% with an additional 30% to 50% of the non-responders becoming responders following a second induction phase. However, BCG’s failure rate for all responders is estimated to be as high as 50% within the first 12 months of treatment and 90% within five years.
For patients who received BCG and whose disease is now BCG-unresponsive, surgical removal of the bladder, or a radical cystectomy has been recommended due to the risk of progression to muscle invasive disease, which greatly reduces a patient’s prognosis. Radical cystectomy is a complex surgery associated with a mortality rate of 8% within six months of surgery. The surgery also entails a number of short-term risks including bleeding and/or clots, infections, bowel obstruction, bowel perforation, peritonitis and injury to the urethra. More than 25% of radical cystectomy patients require hospital readmission for surgery-related complications within 90 days following surgery. The impact of radical cystectomy is life-altering, with major lifestyle changes, including incontinence and sexual dysfunction, and daily issues related to management of the external bag for urine collection.
Keytruda was approved by the FDA in January 2020 for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy and is the only approval of Keytruda in the NMIBC space. Keytruda has been on the market for the treatment of BCG-unresponsive CIS (+/- Ta/T1) patients since January 2020.
In 2009, Endo Pharmaceuticals Inc.'s Valstar (valrubicin) was re-launched in the United States for the treatment of BCG-refractory CIS bladder cancer in patients for whom radical cystectomy is not an option. Valstar is administered directly into the bladder once a week for six weeks. Due to drug resistance and toxicities, Valstar has had limited clinical utility. Other than Keytruda and Valstar, there are no other approved therapies for BCG-unresponsive CIS bladder cancer.
However, there are various other intravesical product candidates in development for the treatment of NMIBC, including product candidates developed by
FerGene Inc. (Adstiladrin/nadofaragene firadenovec (rAd-IFN/Syn3)), AADi, LLC (ABI-009), ImmunityBio (Anktiva/N-803 in combination with BCG),
Theralase Technologies Inc. (TLD-1433),
Janssen (Erdafitinib and TAR-200) and CG Oncology (CG0070).
In addition, systemically-administered checkpoint inhibitors are being evaluated for the treatment of NMIBC including products developed by Bristol-Myers Squibb (Opdivo alone or in combination with BCG +/- BMS986205), F. Hoffmann-La Roche AG (Tecentriq) and AstraZeneca (Imfinzi). Another route of administration for checkpoint inhibitor is currently being evaluated by Pfizer with the subcutaneous administration of Sasanlimab (PF-06801591) for the treatment of BCG-unresponsive NMIBC patients.
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Our Competition
The pharmaceutical industry is highly competitive, subject to rapid and significant technological change and has a strong emphasis on developing proprietary products. While we believe that our next generation TFPT platform, knowledge, experience and scientific resources provide us with competitive advantages, we face competition from both large and small pharmaceutical and biotechnology companies, academic institutions and other research organizations; specifically with companies, institutions and organizations that are actively researching and developing products that attach proprietary cell-killing payloads to antibodies for targeted delivery to cancer cells. Our competitors include, but are not limited to:
•NMIBC:
Merck & Co., Inc. (Keytruda/pembrolizumab and BCG) (approved drugs),
Endo Pharmaceuticals Inc. (Valstar/valrubicin) (approved drug),
FerGene Inc. (Adstiladrin/nadofaragene firadenovec (rAd-IFN/Syn3)),
Medical Enterprises Ltd. (Synergo RITE plus mitomycin C), Aadi, LLC (ABI-009),
ImmunityBio (Anktiva/N-803 in combination with BCG),
CG Oncology. (CG0070),
Theralase Technologies Inc. (TLD-1433 photodynamic compound),
Bristol-Myers Squibb (Opdivo/nivolumab with or without BCG or BMS-986205), F. Hoffmann-La Roche AG (Tecentriq/Atezolizumab),
AstraZeneca (Imfinzi/durvalumab with or without BCG or External Beam Radiotherapy),
Eli Lilly and Company (Gemcitabine) and Telormedix SA (Vesimune);
Pfizer, Inc. (Sasanlimab);