Developer Terminates DHX9 Inhibitor Trial Amid Safety Concerns

Accent Therapeutics has terminated the development of its lead solid tumor candidate, ATX-559, following the emergence of a concerning adverse event profile in a phase 1/2 clinical trial (NCT06625515), according to a report from Fierce Biotech.¹ ATX-559, an oral inhibitor of the DHX9 enzyme, was being investigated as a treatment for patients with advanced or metastatic BRCA1/2-deficient breast cancer or microsatellite instability–high (MSI-H) or deficient mismatch repair (dMMR) solid tumors.

In a previous press release announcing the first patient dosed in the trial of note, Jason Sager, MD, chief medical officer of Accent Therapeutics, said that ATX-559 might be viable as treatment for patients with BRCA1/2-deficient breast cancer who were not responding to PARP inhibitors or MSI-H/dMMR colorectal cancer who were not responding to PD-(L)1 inhibitors.²

Additionally, in April 2025, the FDA granted fast track designation to ATX-559 as treatment for adult patients with dMMR/MSI-H colorectal cancer after checkpoint inhibitor treatment, as well as the developer’s alternative lead candidate, ATX-295, for patients with advanced or metastatic platinum-resistant or refractory ovarian cancer.³

In the release, the developer added that they are currently evaluating “strategic options” for the program.¹ The therapeutic rationale for the program focused on leveraging synthetic lethality in tumors with specific molecular vulnerabilities.

The agent was specifically designed for patients who had developed resistance to established therapies, such as PARP inhibitors in the breast cancer setting or PD-(L)1 inhibitors in the colorectal cancer setting.

The phase 1/2 trial of ATX-559 was a first-in-human, multicenter study that began enrolling patients in December 2024.² The study was designed to evaluate the safety, tolerability, and preliminary anti-tumor activity of the oral inhibitor.³ Eligible participants included adult patients with advanced or metastatic solid tumors that were histologically confirmed to be recurrent or metastatic and were refractory to or relapsed after all standard therapies with proven clinical benefit.⁴ In the expansion cohorts, patients were required to have histological confirmation of either BRCA1/2-deficient, HER2-negative metastatic breast cancer or MSI-H/dMMR unresectable or metastatic solid tumors.

Looking towards the future, the phase 1/2 trial (NCT06799065) for the company’s alternative lead candidate, ATX-295, is currently evaluating that agent's safety in patients with platinum-resistant or refractory ovarian cancer.

A spokesperson for Accent stated that they “are rapidly advancing the ATX-295 phase 1/2 clinical study to build on the promising data supporting ATX-295’s clinical development across multiple solid tumors, including in ovarian cancer, and will continue to expand this trial to other types of cancer with unmet need in the coming year.”¹

That trial is enrolling patients with histologically confirmed solid tumors who have locally recurrent or metastatic disease that is refractory or relapsed after all standard therapies with proven clinical benefit.⁵ In the expansion cohorts, patients were required to have histological confirmation of high-grade serous ovarian carcinoma that is platinum resistant, platinum refractory, or platinum intolerant.

Excluded patients were those with clinically unstable central nervous system tumors or brain metastasis, any other non-hormonal blockade concurrent anti-cancer treatment, clinically significant or uncontrolled cardiovascular disease, and inability to transition off strong or moderate CYP3A4 inhibitors or strong inducers, among others.

ATX-295 will be administered orally to all patients in the trial. The primary end points of the trial are the recommended phase 2 dose, maximum tolerated dose, and incidence of treatment-emergent adverse events. Secondary end points include preliminary evidence of antitumor activity and pharmacodynamics.

References

1. Waldron J. Accent halts solid tumor trial over adverse events, pivots to other lead cancer program. Fierce Biotech. February 26, 2026. Accessed February 26, 2026. https://tinyurl.com/ms72ndr3
2. Accent Therapeutics announces first patient dosed in phase 1/2 trial of ATX-559 and chief scientific officer transition. News release. Accent Therapeutics. December 11, 2024. Accessed February 26, 2026. https://tinyurl.com/p4jube57
3. Accent Therapeutics announces first patient dosed in Phase 1/2 trial of novel KIF18A inhibitor ATX-295 and receives FDA fast track designation for lead assets ATX-295 and DHX9 inhibitor ATX-559. News release. Accent Therapeutics. April 15, 2025. Accessed February 26, 2026. https://tinyurl.com/yc6y4rsr
4. First-in-human study of ATX-559, an oral inhibitor of DHX9, in patients with advanced or metastatic solid tumors, and molecularly defined cancers. ClinicalTrials.gov. Updated February 24, 2026. Accessed February 26, 2026. https://tinyurl.com/nd32uw5b
5. First-in-human study of ATX-295, an oral inhibitor of KIF18A, in patients with advanced or metastatic solid tumors, including ovarian cancer. ClinicalTrials.gov. Updated February 24, 2026. Accessed February 26, 2026. https://tinyurl.com/y76u43pd