Tango Halts USP1 Inhibitor Due to Liver Toxicity in Phase 1 Trial

Tango Therapeutics has decided to halt the development of its cancer drug TNG348 after it was associated with instances of liver toxicity in a phase 1 clinical trial. The company was testing the safety and efficacy of TNG348 in patients with BRCA1/2 mutations and other cancers characterized by homologous recombination deficiency (HRD+). The original plan involved combining TNG348 with Lynparza, a PARP inhibitor developed by AstraZeneca and Merck & Co., for a more effective treatment. However, the trial did not progress to this combined treatment phase.

The decision to terminate the TNG348 program came after the observation of grade 3 and 4 liver function abnormalities in patients who remained in the study for over eight weeks. Grade 4 abnormalities are considered life-threatening. Barbara Weber, M.D., CEO of Tango Therapeutics, emphasized that patient safety is the company's top priority, stating, "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." Despite the setback, Weber maintained that this decision was the most prudent course of action given the current data.

USP1, the target of TNG348, is a deubiquitinating enzyme involved in DNA damage response, representing a novel approach to cancer treatment known as synthetic lethality. This approach has gained traction over the past decade, largely due to the success of PARP inhibitors like Lynparza. However, while PARP inhibitors have proven effective in many cases, they do not work for all patients and can eventually lead to resistance.

In light of the TNG348 setback, Tango Therapeutics will redirect its focus and resources to other programs in its pipeline, particularly its PRMT5 program. The leading candidate in this program, TNG908, is undergoing phase 1/2 clinical trials in patients with MTAP-deleted tumors. Another PRMT5 candidate, TNG462, is also in early-phase trials for various tumor types. Weber expressed confidence in these remaining programs, noting, "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."

Additionally, Tango Therapeutics has an ongoing collaboration with Gilead Sciences that encompasses 15 immuno-oncology targets. This partnership has been a cornerstone of Tango's strategy to expand its therapeutic portfolio.

The news of the TNG348 program discontinuation had an immediate impact on Tango Therapeutics' stock price, which dropped by 5.3% in premarket trading to $7 as of early Thursday morning.

In summary, while the termination of the TNG348 program due to liver toxicity is a significant setback, Tango Therapeutics remains committed to advancing its other promising programs and partnerships in the field of oncology.