USP1

Exelixis said its tissue factor (TF)-targeting antibody-drug conjugate “is unlikely to improve upon” tisotumab vedotin—an approved TF-focused ADC marketed for cervical cancer as Tivdak. Exelixis is giving up on its tissue factor (TF)-targeting antibody-drug conjugate after concluding the candidate was unlikely to best Pfizer and Genmab’s Tivdak.The biotech had been evaluating the ADC, dubbed XB002, in the phase 1 JEWEL-101 trial in advanced solid tumors and said that it would unveil the data “at a later date.” But, based on what the company has seen so far, Exelixis said the compound “is unlikely to improve upon” tisotumab vedotin—an approved TF-focused ADC marketed for cervical cancer as Tivdak—“or other competitor TF-targeting ADCs currently in development.”Resources from the XB002 program will be reallocated to the late-stage tyrosine kinase inhibitor zanzalintinib, as well as the phase 1 USP1 inhibitor XL309 and the biotech’s “growing pipeline,” Exelixis said in its second-quarter earnings release.Exelixis isn’t ready to give up on ADCs quite yet. The company pointed out that XB371, its ADC consisting of a topoisomerase payload conjugated to a TF-targeting monoclonal antibody, remains in preclinical development.In his statement to accompany the release, Exelixis CEO Michael Morrissey, Ph.D., focused the spotlight on Cabometyx, which is already approved for renal cell carcinoma, hepatocellular carcinoma and thyroid cancer. The Ipsen-partnered tyrosine kinase inhibitor brought in $433.3 million in net U.S. revenues in the second quarter and the FDA is mulling an application to approve the drug in advanced neuroendocrine tumors (NETs). “We’re actively preparing for launch and excited at the prospect of bringing this new treatment option to previously treated advanced NET patients with high unmet medical need,” Morrissey said.“At the same time, we are prioritizing our clinical pipeline with plans to initiate a new phase 3 pivotal trial for zanzalintinib in NET, advance phase 1 efforts for XL309 and XB010, and discontinue development of XB002,” the CEO added.“In our view, Exelixis enters 2024 at an inflection point, in which the growth of its flagship Cabometyx franchise is stabilizing while pipeline programs, especially zanzalintinib, are holding increasing responsibility to offset Cabometyx’s market exclusivity expiry in 2031,” William Blair analysts said in an Aug. 7 note.“In the midterm, NETs and [metastatic castration-resistant prostate cancer] could emerge as material growth opportunities for the franchise,” the analysts added.It’s been a year of change at Exelixis, which laid off 175 employees—equivalent to around 13% of its workforce—in January as part of a broader restructuring aimed at “concentrate[ing] R&D resources to advance our emerging pipeline.”At the time, that strategy included progressing XB002 through a phase 1 trial. Exelixis had licensed the ADC from Iconic Therapeutics back in 2020, citing preclinical data that supported the asset’s “best-in-class potential in treatment of solid tumors.”

“While disappointing, we believe this is the right decision given the data at hand,” Tango's CEO said. Tango Therapeutics has discarded one of its cancer drugs on the dancefloor after the USP1 inhibitor was linked to reports of liver toxicity in a phase 1 trial. The biotech had been testing the safety and efficacy of the candidate, dubbed TNG348, in a phase 1/2 study in patients with BRCA1/2-mutant and other HRD+ cancers. The plan had been to add AstraZeneca’s and Merck & Co.’s PARP inhibitor Lynparza into the mix as a combo treatment, but the study never made it that far. Instead, Tango has decided to end the trial—and the TNG348 program entirely—after grade 3/4 “liver function abnormalities” were observed in patients who continued on the study for longer than eight weeks. A grade 4 event is considered life-threatening.  “Patient safety is always our first priority and based on emerging data from the TNG348 dose escalation study, we have made the decision to discontinue further development of this molecule due to liver toxicity experienced by patients in the trial,” Tango’s CEO Barbara Weber, M.D., said in the May 23 release. “While disappointing, we believe this is the right decision given the data at hand,” Weber added. USP1, a deubiquitinating enzyme that regulates DNA damage response, is one of a number of emerging targets for synthetic lethality, an approach to killing cancer cells that PARP inhibitors such as Lynparza have helped put on the map over the past decade. While PARP inhibitors have validated the concept, they are unable to trigger responses in all patients and are vulnerable to resistance even when they are initially effective. Last year, Roche inked a deal to secure an exclusive global license to KSQ Therapeutics’ early-phase USP1 inhibitor. With Tango’s own USP1 ambitions up in smoke, Weber said the company will focus resources on its remaining portfolio, which is headed up by a PRMT5 program. The lead candidate, TNG908, is being assessed in a phase 1/2 in patients with MTAP-deleted tumors. Another PRMT5 drug, TNG462, is also in phase 1/2 development for various tumor types. “We remain committed to and confident in our ability to deliver a comprehensive clinical update on TNG908 and TNG462 in the second half of this year,” Weber said. Tango also has a dance partner in the form of Gilead, with a long-standing collaboration that stretches to 15 immuno-oncology targets. The biotech's shares were trading down premarket by 5.3% to $7 as of 7:12 am ET on Thursday morning.

Just months after starting a Phase I/II trial of its solid tumour candidate TNG348, Tango Therapeutics said Thursday that it will discontinue development of the USP1 inhibitor because several participants experienced liver toxicities.The study enrolled patients with BRCA1/2-mutant and other homologous recombination deficient cancers and dosed the first participant with TNG348 in January. According to Tango, grade 3/4 liver function abnormalities were observed in patients who remained on the study for more than eight weeks. “Patient safety is always our first priority and based on emerging data from the TNG348 dose escalation study, we have made the decision to discontinue further development of this molecule due to liver toxicity experienced by patients in the trial,” CEO Barbara Weber said in a statement. TNG348 was in-licensed in 2020 from Medivir, who was eligible for development and commercial milestones on the programme, as well as royalties.The company’s portfolio now includes three clinical assets in Phase I/II studies for cancer: TNG908 and TNG462, which both inhibit PRMT5; and TNG260, a highly selective CoREST complex inhibitor.