FDA Awards Orphan Drug Status to ZEN-3694 for NUT Carcinoma

The FDA has granted orphan drug designation to ZEN-3694, a novel oral therapy, for the treatment of NUT carcinoma.¹

The FDA’s orphan drug designation is awarded to new treatments for rare conditions affecting fewer than 200,000 people in the US.² NUT carcinoma, with an estimated incidence of 10,000 cases per year¹ and poor median survival of 6 to 9 months, is a rare, aggressive cancer that is potentially underdiagnosed due to lack of awareness.³ Currently, no therapies are approved for NUT carcinoma, restricting treatment options for patients.

ZEN-3694 is a potent, selective BET bromodomain inhibitor that disrupts the activity of NUT fusion protein, which is implicated in promotion of tumor growth.⁴ Its mechanism of action is anticipated to slow or prevent tumor growth as well as potentially shrink or stabilize the cancer. As such, the designation of orphan drug status represents a significant milestone in ZEN-3694’s development pathway, offering hope for patients with this critical unmet need.

“Orphan [d]rug status underscores the unmet need for novel treatment options in this rare disease, where patients face poor prognoses and currently have no approved targeted therapies,” said Donald McCaffrey, president & CEO of Zenith Epigenetics, in a press release.¹ “We believe ZEN-3694, through its epigenetic mechanism and combinatorial approach, has the potential to significantly improve outcomes and survival for people with NUT carcinoma. Orphan [d]rug designation, and the recently announced [f]ast [t]rack designation, help us advance this program with the goal of making ZEN-3694 available to those who may benefit from it.”

About the Clinical Development of ZEN-3694

In July 2025, ZEN-3694, in combination with abemaciclib (Verzenio), was granted FDA fast track designation in patients who have received at least 1 prior line of chemotherapy, accelerating clinical development for this crucial therapy. The designation for this combination was grounded in positive preliminary combination efficacy, including superior response rate and duration of response compared with single agent BET inhibitors.¹

This synergistic combination is being investigated in an ongoing, actively recruiting dose-escalation and dose-expansion phase 1 study (NCT05372640) evaluating safety of the combination in metastatic or unresectable NUT carcinoma, breast cancer, and other solid tumors.⁵ With a total estimated enrollment of 45 patients, its primary goals are to determine the maximum tolerated dose and recommended phase 2 dose; secondary goals include assessing preliminary antitumor activity and characterizing the combination’s pharmacokinetic profile. The study is estimated to be completed by June 2026.

Additionally, an ongoing recruiting phase 1/2 trial (NCT05019716) is exploring the agent in combination with chemotherapy drugs cisplatin and etoposide in patients with NUT carcinoma, specifically investigating the tumor shrinkage potential of this combination.⁶ This trial aims to enroll 55 patients and is also slated for completion by June 2026.

Together, these trials will further elucidate the safety and efficacy of ZEN-3694 administered in various therapeutic formats.

REFERENCES:

1. Zenith Epigenetics’ ZEN-3694 Receives Orphan Drug Designation from FDA. News release. Zenith Epigenetics. October 27, 2025. Accessed October 29, 2025. https://tinyurl.com/bdhvzh7e

2. Designating an Orphan Product: Drugs and Biological Products. US Food & Drug Administration. Updated August 12, 2024. Accessed October 29, 2025. https://tinyurl.com/5n77pu2w

3. Lauer UM, Hinterleitner M, Horger M, et al. NUT Carcinoma—An Underdiagnosed Malignancy. Front Oncol. 2022;12. doi.org/10.3389/fonc.2022.914031

4. FDA grants Zenith’s ZEN-3694 Fast Track Status. News release. Zenith Epigenetics. July 14, 2025. Accessed October 29, 2025. https://tinyurl.com/4s7axts9

5. Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors. ClinicalTrials.gov. Updated September 19, 2025. Accessed October 29, 2025. https://clinicaltrials.gov/study/NCT05372640

6. Testing the Safety and Efficacy of the Addition of A New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Etoposide and Cisplatin) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma. ClinicalTrials.gov. Updated September 3, 2025. Accessed October 29, 2025. https://clinicaltrials.gov/study/NCT05019716