Accent Therapeutics halts study of first-in-class DHX9 molecule after safety findings

US-based Accent Therapeutics has terminated the sole clinical trial for ATX-559, an oral inhibitor of the RNA helicase DHX9, after enrolling 17 patients with advanced solid tumors, according to an update to the ClinicalTrials.gov registry (NCT06625515). The sponsor cited the adverse event profile observed during dose escalation as the reason for halting the study.

As per the source, the first-in-human trial was an open-label, non-randomized, sequential dose-escalation and expansion study designed to identify a recommended Phase II dose and maximum tolerated dose. The trial was initiated in October 2024 with an enrolment target of 17, and set a completion date of January 9, 2026. Eligible participants included adults with histologically confirmed locally advanced or metastatic solid tumors who had exhausted standard therapies.

Expansion cohorts were planned for patients with BRCA1/2-deficient HER2-negative metastatic breast cancer and for those with microsatellite instability-high or mismatch repair-deficient solid tumors. Primary endpoints focused on safety and tolerability, including dose-limiting toxicities and adverse events graded per CTCAE v5.0. Secondary endpoints included objective response rate by RECIST v1.1, pharmacokinetics, and circulating BRIP1 RNA as a pharmacodynamic marker of on-target DHX9 inhibition.

The study terminated prior to its planned primary completion date of January 2026. The registry record does not disclose the nature or severity of the adverse events that led to discontinuation, and no clinical efficacy data have been reported.

ATX-559 had been the only DHX9 inhibitor to enter clinical testing, targeting a helicase involved in resolving R-loops — three-stranded nucleic acid structures formed during transcription and replication. The development rationale centered on synthetic lethality, based on the hypothesis that tumors with underlying DNA repair deficiencies or elevated replication stress, including BRCA1/2-mutant or dMMR cancers, may depend on DHX9 function to manage R-loop accumulation.

Inhibiting DHX9 was intended to increase replication stress beyond tolerable levels in these cells, inducing tumor-selective DNA damage. A search of major clinical trial registries does not identify other DHX9-targeting agents currently in human studies, leaving the target without an active clinical program following ATX-559’s termination.

Accent Therapeutics continues to advance other pipeline assets, including the preclinical KIF18A inhibitor ATX-295, and maintains an ongoing collaboration with AstraZeneca on RNA-modifying protein programs not involving DHX9.

Replication stress-targeting approaches remain an active area of oncology drug development, including ATR and WEE1 inhibitors under investigation in overlapping patient populations. However, it is unclear from available data whether the safety findings associated with ATX-559 reflect a liability intrinsic to DHX9 inhibition or compound-specific pharmacologic properties.