Advancing Metastatic Breast Cancer Treatment: Z-Endoxifen Nears IND Submission

Atossa Therapeutics, a clinical-stage biopharmaceutical company, has received positive written feedback from the US FDA regarding its proposed dose optimization trial for Z-endoxifen.¹ This critical regulatory interaction, occurring prior to a scheduled pre-investigational new drug (IND) meeting, has effectively cleared the path for an anticipated IND submission in the fourth quarter of 2025.

The drug is being developed for the treatment of estrogen receptor positive (ER+), HER2-negative (–) metstatic breast cancer, representing a significant stride toward a new therapeutic option for this patient population.The FDA's feedback serves as a strong endorsement of Atossa's comprehensive clinical development strategy for Z-endoxifen.

“"These FDA responses mark a significant milestone for the Company and are supportive of our comprehensive approach to developing (Z)-endoxifen for metastatic breast cancer," said Steven Quay, MD, Atossa's CEO and chairman of the board, in a press release. "The detailed feedback received significantly advances our goal of submitting an IND by year-end. Importantly, the FDA's support of our dose optimization strategy and general agreement with our nonclinical data package leave us confident in our scientific rationale and overall regulatory approach."

A pivotal aspect of the FDA's feedback centered on the proposed dose-optimization study. The agency concurred that the available clinical and nonclinical data are sufficient to initiate the monotherapy part A of the study, providing specific guidance on randomization cohort sizes and refinements for the overall study design. This agreement is crucial for efficiently progressing Z-endoxifen into later-stage clinical trials, ensuring that the optimal dose is identified to maximize efficacy while minimizing potential toxicities, a principle central to the FDA's Project Optimus initiative. Project Optimus emphasizes data-driven dose exploration to define the optimal dose for combination therapies, and Atossa intends to explore multiple dose levels to meet this objective.²

Beyond monotherapy, the FDA also expressed support for the scientific rationale underpinning combination studies of Z-endoxifen with established breast cancer standard-of-care therapies.¹ This includes CDK4/6 inhibitors, PI3K inhibitors, mTOR inhibitors, and capecitabine. This regulatory alignment on combination strategies will enable Atossa to narrow its strategic approach for the impending IND, potentially accelerating the development of Z-endoxifen as part of a multidrug regimen. The ability to combine with existing effective treatments could significantly broaden the therapeutic utility of enclomiphene for patients with advanced ER+/HER2– metastatic breast cancer.

Furthermore, the FDA deemed the existing nonclinical safety data package for Z-endoxifen adequate, indicating that no additional general toxicity or neurotoxicity studies are required to proceed. This reduces the preclinical burden and allows for a more streamlined progression into human trials. The agency also confirmed the sufficiency of Atossa's cardiac safety assessment plan for the monotherapy portion of the trial, including serial electrocardiograms and QT interval monitoring. These confirmations are vital, as they address key safety considerations early in the development process, providing a clearer path forward for clinical investigation.

Z-endoxifen is characterized as a highly potent selective estrogen receptor modulator (SERM). Its mechanism of action involves inhibiting and potentially degrading estrogen receptors, which is particularly relevant for ER+ breast cancers. Notably, Z-endoxifen has demonstrated activity even in tumors that have developed resistance to other forms of endocrine therapy.

Beyond its SERM activity, it also targets PKCβ1 and has shown comparable or superior bone-protective effects when compared to tamoxifen (Soltamox), another widely used endocrine therapy. Atossa is developing a proprietary oral, enteric-coated formulation of Z-endoxifen to ensure optimal bioavailability, which is critical for consistent drug exposure and efficacy.

To date, clinical studies involving over 700 patients have demonstrated that Z-endoxifen is well tolerated, with no maximum tolerated dose identified up to 360 mg/day. Atossa is currently prioritizing the development of Z-endoxifen for metastatic breast cancer and is evaluating its potential in 3 ongoing phase 2 trials.

REFERENCES:

1. Atossa Therapeutics Announces Positive FDA Feedback, Advances Toward IND for (Z)-Endoxifen Clinical Program in ER+/HER2- Metastatic Breast Cancer. News release. Atossa Therapeutics. July 29, 2025. Accessed July 30, 2025. https://tinyurl.com/4ud6yrwa

2. Project Optimus. US FDA. Updated December 6, 2024. Accessed July 30, 2025. https://tinyurl.com/5dkj48tr