Tango Halts Cancer Trial Due to Liver Toxicity, Exits Race Against Roche

Tango Therapeutics has announced the cessation of its development of TNG348, a synthetic lethal cancer drug, following liver toxicity concerns in patients. This decision comes after the biotech company initiated a Phase I clinical trial of the USP1 inhibitor TNG348 in December 2023, targeting solid tumors.

The clinical trial aimed to investigate increasing doses of TNG348, first as a monotherapy and later in combination with the PARP inhibitor Lynparza (olaparib). However, liver function abnormalities observed in patients led to the study's premature termination before reaching the combination phase. Specifically, patients who remained in the trial for over eight weeks exhibited Grade 3 and 4 liver function abnormalities. The trial focused on individuals with BRCA1/2-mutant and other homologous recombination deficient cancers.

USP1, a deubiquitinating enzyme, plays a crucial role in regulating the DNA damage response (DDR). This function made it a candidate for synthetic lethality studies, where the simultaneous loss of two genes results in cell death. Preclinical evidence suggested that USP1 inhibitors could work synergistically with PARP inhibitors, such as Lynparza, enhancing therapeutic effects in patients either naïve or resistant to PARP inhibitors. This potential drew the interest of several companies, including Roche, which licensed a leading USP1 inhibitor from KSQ Therapeutics in 2023.

Despite Tango's setback, other developers of USP1 inhibitors have not reported similar liver toxicity issues. For example, Roche began a Phase I trial of its USP1 inhibitor in August 2021. Although enrollment paused for several months in 2023 for undisclosed reasons, no safety issues were reported. Similarly, Exelixis's USP1 inhibitor, ISM3091, licensed from Insilico Medicine, entered clinical trials in August 2023 and has proceeded without interruption.

The shared characteristics among USP1 inhibitors were highlighted by Tango CEO Barbara Weber during a Barclays event in March 2024. Weber noted the similarities in the leading USP1 inhibitors, attributing this to the necessity of targeting a single allosteric site to inhibit the enzyme. "The only way we and others have found to inhibit USP1 is through a single allosteric site. So, you might imagine that there's a fair amount of similarity in the molecules that have that mechanism of action," Weber explained. She emphasized the importance of clinical data and pharmacokinetics in understanding the differences and potential safety profiles of the inhibitors.

As Tango Therapeutics investigates the underlying reasons for the liver function abnormalities observed in its trial, the future of USP1 inhibitors remains uncertain yet promising. With continued research and trials from other developers, the potential therapeutic benefits of targeting USP1 in cancer treatment may still be realized.

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