Tango Therapeutics reported Thursday that solid tumor patients who stayed in the Phase I study for more than eight weeks developed Grade 3 and 4 liver function abnormalities.
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.
