The U.S. Food and Drug Administration has granted Orphan Drug designation to ZEN-3694 for the treatment of NUT carcinoma, marking a significant regulatory milestone for Zenith Epigenetics' lead compound in addressing a rare cancer with no approved therapeutic options. The designation underscores the urgent medical need for novel treatments in this aggressive malignancy that affects both adults and children.
Addressing Critical Unmet Medical Need
NUT carcinoma represents one of the most challenging oncological conditions, with patients facing a median overall survival of approximately 6 months. The cancer typically occurs in the midline areas of the body, including head, neck, and thoracic regions, and is characterized by its highly aggressive nature. Despite being classified as rare, the actual incidence is estimated at 10,000 cases per year in G8 countries, though the condition remains significantly underdiagnosed due to lack of awareness and limited testing capabilities.
"Orphan Drug 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. "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."
ZEN-3694's Mechanism and Clinical Development
ZEN-3694 functions as a potent and selective BET bromodomain inhibitor, administered orally once daily. The compound targets the underlying molecular mechanism of NUT carcinoma, where the NUTM1 gene fuses with transcriptional regulators, most commonly BET proteins, driving the expression of cancer-causing genes and leading to unchecked tumor growth. By disrupting the activity of NUT fusion proteins, ZEN-3694 has demonstrated both single-agent and combination efficacy in treating the disease.
The drug's safety profile has been established through dosing over 550 patients to date, yielding robust evidence of on-target safety that enables chronic dosing and combinability with other targeted therapies. This extensive safety database positions ZEN-3694 as a differentiated BET inhibitor in the competitive landscape.
Active Clinical Trial Programs
Zenith is currently evaluating ZEN-3694 in two active NUT carcinoma clinical trials. The first study (ClinicalTrials.gov ID: NCT05372640) combines ZEN-3694 with abemaciclib, while the second trial (ClinicalTrials.gov ID: NCT05019716) evaluates the combination with cisplatin and etoposide. Early results from the abemaciclib combination have shown superior response rates and duration of response compared to single-agent BET inhibitors, primarily by preventing therapy resistance.
Beyond NUT carcinoma, Zenith is advancing ZEN-3694 in metastatic castration-resistant prostate cancer through a partnership with Newsoara. The companies have initiated a 200-patient Phase 2b randomized trial comparing ZEN-3694 plus enzalutamide versus single-agent enzalutamide, with approximately 178 patients enrolled since the first patient was dosed in December 2021.
Regulatory Advantages and Strategic Positioning
The Orphan Drug designation provides Zenith with several strategic advantages, including potential seven-year market exclusivity following approval, tax credits for qualified clinical trials, and exemption from FDA user fees. These incentives complement the previously announced Fast Track designation for ZEN-3694, with the company stating its intention to pursue Breakthrough Therapy designation.
The regulatory recognition comes as Zenith representatives attend the World Orphan Drug Congress 2025 in Amsterdam, the largest orphan drug and rare disease meeting with over 2,000 professionals from the rare disease community, including pharmaceutical and biotechnology executives and patient advocates.
Broader Development Pipeline
Zenith Epigenetics, a wholly owned subsidiary of Zenith Capital Corp., maintains a comprehensive clinical development program for ZEN-3694 across multiple oncology indications, including ovarian cancer, colorectal cancer, breast cancer, squamous cell lung cancer, and other solid tumors. Several studies are sponsored by the National Cancer Institute under Cooperative Research & Development Agreements, highlighting the compound's potential across diverse cancer types with significant unmet medical needs.
