TNG-348

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.

Pictured: Illustration of a human body with the liver highlighted/iStock, magicmine Tango Therapeutics said Thursday it has stopped development of an early-phase synthetic lethal cancer candidate after seeing liver toxicity in recipients of the molecule. The biotech began a Phase I clinical trial of the USP1 inhibitor TNG348 in solid tumors in December 2023. Tango planned to study escalating doses of TNG348, initially as a single agent and then in combination with the PARP inhibitor Lynparza (olaparib). However, a safety signal prompted the company to stop the study before reaching the combination cohort. Investigators saw Grade 3 and 4 liver function abnormalities in patients who stayed in the study for more than eight weeks. The trial was testing TNG348 in patients with BRCA1/2-mutant and other homologous recombination deficient cancers. USP1 is a deubiquitinating enzyme that regulates DNA damage response (DDR). The enzyme’s role in DDR led researchers to study its potential in synthetic lethality, a genetic interaction when the loss of two genes leads to cell death. Preclinical studies suggest inhibitors of the enzyme work synergistically with inhibitors of PARP, the target of the pioneering synthetic lethal drug Lynparza. Early evidence that targeting USP1 may enhance the effect of drugs such as Lynparza in patients who are naïve or resistant to PARP inhibitors has attracted a small group of companies. Roche is the biggest name in the space. The Swiss drugmaker licensed the most advanced USP1 inhibitor from KSQ Therapeutics in 2023. Tango has yet to share a hypothesis for why patients had liver function abnormalities. Other developers of USP1 inhibitors appear to have avoided such problems so far. Researchers started a Phase I clinical trial of Roche’s candidate in August 2021. Enrollment stopped for several months in 2023 for an undisclosed reason but there have been no reports of safety problems. ISM3091, the USP1 inhibitor Exelixis licensed from Insilico Medicine, entered the clinic in August 2023 and the trial has continued uninterrupted. The molecules and other preclinical USP1 inhibitors share key characteristics. Tango CEO Barbara Weber discussed the similarities between the seven leading USP1 inhibitors at a Barclays event in March 2024. “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 said. “I think we just have to see what the clinical data looks like. The [pharmacokinetics] ends up being an important component of that.” Nick Paul Taylor is a freelance pharmaceutical and biotech writer based in London. He can be reached on LinkedIn.