Advanced Urothelial Carcinoma

Tyra Biosciences unveiled early trial results on its FGFR3-specific inhibitor in advanced bladder cancer patients on Friday, the public company’s first presentation of human data since its inception in 2018. The biotech’s data were highly anticipated: Its shares $TYRA were up over 100% ahead of the readout, but they fell 18% Friday morning on the update. While the company tested a range of doses in the Phase 1 portion of its SURF301 study in metastatic urothelial carcinoma, its efficacy results focused on the patients who received at least 90 mg, where it believes the drug achieved “adequate target coverage.” Five of the 10 patients who received a 90 mg daily dose of TYRA-300 achieved a partial response, as did one patient who received a 120 mg dose. According to Tyra, three of those six responses are still ongoing. The company said 41 patients with FGFR3+ cancer have enrolled as of Aug. 15, including those who were previously treated with Johnson & Johnson’s Balversa. Tyra’s ultimate goal is to develop a safer treatment than Balversa, which in 2019 became the first FGFR-targeted drug to receive FDA accelerated approval for bladder cancer and earlier this year was granted full approval in advanced FGFR3+ urothelial carcinoma. In its confirmatory trial, Balversa resulted in a response rate of 35% in FGFR3+ advanced bladder cancers. TYRA-300, which goes only after FGFR3 while sparing other isoforms (FGFR1/2/4), aims to evade or lessen certain side effects including eye problems, mouth sores and inflammation, and increased phosphate levels. As we started to see a profile and hear from investigators that this was a really well-tolerated drug, we got really excited that the sparing of FGFR1 and 2 thesis could play out,” CEO Todd Harris said of the safety data in an interview with Endpoints News . The biotech said in a release that SURF301 patients experienced “infrequent FGFR2- and FGFR1-associated toxicities.” TD Cowen analyst Tyler Van Buren wrote in a note Friday that “TYRA-300 boasts a superior tolerability profile compared to pan-FGFR inhibitors,” like Balversa. In 15 patients at the 90 mg dose, the most common adverse events were liver enzyme increases and dry mouth, which 6 trial participants experienced. One grade 3 case of elevated liver enzyme levels resulted in treatment discontinuation and one grade 3 case of diarrhea was reported as a dose-limiting toxicity at 90 mg. “These data give us confidence to advance TYRA-300 through Part B in SURF301 and explore larger opportunities with Phase 2 studies in metastatic urothelial cancer, non-muscle invasive bladder cancer and achondroplasia,” said Tyra CEO Todd Harris in a statement. Harris told Endpoints News that for both non-muscle invasive bladder cancer and achondroplasia, a form of dwarfism, Tyra expects to test lower doses of TYRA-300 than the 90 mg it highlighted in urothelial carcinoma.

Following a disappointing confirmatory clinical trial, Gilead Sciences has officially decided to withdraw its product Trodelvy from the bladder cancer treatment market in the United States. The decision was announced Friday by the California-based biotechnology company after extensive discussions with the U.S. Food and Drug Administration (FDA). This directly affected the accelerated approval status of Trodelvy in a specific patient population - those with advanced urothelium carcinoma who had previously received PD-1/L1 inhibitors and chemotherapy. Gilead emphasized that despite the setbacks in bladder cancer, Trodelvy remains effective in other indications for breast cancer in the United States. The divestment did not come without warning. Back in May, Gilead had already heralded the substandard results of the troics-04 study, which was intended as a confirmative trial for Trodelvy in bladder cancer. Specifically, the TROP2-directed antibo-drug conjugate failed to demonstrate efficacy over conventional chemotherapy in extending survival in certain bladder cancer patients. So far, details about the failed test have not been made public. Looking back at history, Trodelvy received approval for a bladder cancer treatment in 2021 based on positive data from a single-arm Phase 2 clinical trial. At that time, the drug triggered a tumor response in 27.7 percent of patients, with 5.4 percent achieving a complete response and a median response duration of 7.2 months. Gilead's chief financial officer, Andrew Dickinson, noted during the company's second-quarter earnings call in August that bladder cancer treatment is a relatively small part of Trodelvy's many indications, contributing less than 10% of sales. The first-of-its-kind TROP2 ADC drug generated $320 million in sales for Gilead in the three months ended June. It is important to note that Trodelvy's failure in the bladder cancer field was not an isolated incident, it came on the heels of the failure of another key trial, the IUX-01 study. Trodelvy also failed to achieve significant results in a trial comparing chemotherapy with second-line non-small cell lung cancer (NSCLC). As a result of the setback, Gilead took a $2.4 billion impairment charge. Trodelvy's performance has been highly anticipated as a core asset in Gilead's $21 billion acquisition of Immunomedics in 2020. The successive failures of two important trials have certainly clouded Trodelvy's prospects. Once upon a time, Trodelvy was expected to be the cornerstone of Gilead's solid tumor franchise. However, as competitors such as Astrazeneca and Daiichi Sankyo, Merck and Kelun Biotech advance their respective TROP2 ADCs and pursue extensive Phase III programs, Trodelvy's first-mover advantage is gradually being eroded. Looking ahead, Trodelvy's next major milestone will be the results of the IUX-03 trial. The trial is evaluating Gilead's drug in combination with Merck's PD-1 inhibitor Keytruda in patients with NSCLC with high PD-L1 expression. The trial started in February 2023 and is expected to be primarily completed in January 2027. At the same time, with the shift in first-line bladder cancer treatment options - particularly Keytruda in combination with Pfizer and Astellas Nectin-4 ADC drug Padcev in favor - Trodelvy's exit from the bladder cancer space is particularly notable. This shift has sparked a new round of discussion about Trodelvy's status as a PD-1/L1 inhibitor and post-chemotherapy treatment. Faced with an increasingly stringent regulatory review environment by the FDA, biopharmaceutical companies often tend to act quickly after the failure of confirmatory trials to withdraw expedited approval of related products. There have been several examples of this trend in recent years: GlaxoSmithKline withdrew its multiple myeloma ADC from Blenrep just days after its Phase 3 trial failed; Takeda voluntarily withdrew its lung cancer drug Exkivity about two months after receiving negative confirmation; And last month Pfizer abruptly pulled its sickle cell drug Oxbryta from global shelves over safety data.

Gilead Sciences is voluntarily withdrawing cancer drug Trodelvy from the U.S. market as a treatment for advanced cases of urothelial carcinoma, a move that comes nearly five months after the therapy’s failure in a confirmatory study. Gilead made the decision in consultation with the FDA, the company said in its announcement Friday. The withdrawal in metastatic urothelial carcinoma, an aggressive form of bladder cancer, does not affect the drug’s status in its other approved indications in the U.S. as well as other markets. Foster City, California-based Gilead said clinicians will be notified of Trodelvy’s withdrawal in urothelial carcinoma, adding that patients who have this type of cancer should discuss their treatment options with their provider. ` Trodelvy is an antibody drug conjugate (ADC), a type of therapy comprised of a targeting antibody linked to a toxic drug payload. ADCs’ ability to offer targeted way of killing cancer cells has made this drug class one of the hottest areas of cancer drug research. The target of Trodelvy Gilead drug is TROP-2, a protein abundant on the surface of many types of cancer cells. In 2021, the FDA awarded Trodelvy accelerated FDA approval for treating cases of urothelial carcinoma that is locally advanced or metastatic after treatment with chemotherapy or a type of immunotherapy called a checkpoint inhibitor. This approval was based on Phase 2 data measuring tumor response rate and duration of response. Drugs that reach the market through the accelerated approval pathway must confirm their safety and efficacy in a larger and longer Phase 3 confirmatory study. sponsored content Upcoming Webinar: Battle of the Budget: Employers vs. Rising Healthcare Costs Gain valuable knowledge and practical insights on how employers are addressing an increasingly complex healthcare budget landscape. By Personify Health This past May, Gilead announced Trodelvy failed its confirmatory test in urothelial carcinoma with results that fell short of statistical significance against the main goal of measuring overall survival. The company did not disclose more detail, saying only that data would be presented at a medical meeting. The data still have not been presented, but Gilead on Friday reiterated its pledge to present them at an unspecified upcoming medical meeting. Trodelvy first reached the market in 2020 as a treatment for advanced cases of triple negative breast cancer. In 2021, the drug converted its accelerated approval to a full approval in this indication. Last year, Trodelvy expanded its label with accelerated approval for treatment of advanced HR positive HER2 negative breast cancer. But Gilead has encountered setbacks in its efforts to expand the drug’s label. At the beginning of this year, Gilead reported Trodelvy failed a Phase 3 test in non-small cell lung cancer. Across all of its approved indications, Trodelvy accounted for more than $1 billion in sales in 2023, according to Gilead financial reports. In the first half of this year, the drug generated $628 million in revenue, a 30% increase compared to the same period in 2023. The company attributed the sales growth to higher demand in both of its approved breast cancer indications. Gilead says Trodelvy has approvals in more than 50 countries. The drug’s clinical development program includes tests in other populations of breast cancer patients as well as lung cancer, head and neck cancer, and gynecological cancers.