FDA Pushes Z-Endoxifen Toward Next Step in Breast Cancer Treatment

The FDA has issued a “Study May Proceed” letter for the study of patients with metastatic breast cancer being treated with Z-endoxifen.¹

Atossa Therapeutics, the developer of the agent and study, received an investigational new drug (IND) application for Z-endoxifen, a selective estrogen receptor (ER) modulator.

“This letter marks an important regulatory milestone for Atossa and to potentially expand the use of Z-endoxifen for metastatic ER-[positive]/HER2-[negative] [b]reast [c]ancer,” said Steven Quay, MD, PhD, Atossa Therapeutics president and CEO, in a news release. “We believe its activity, even in tumors that have developed resistance to other endocrine therapies and in the oncogenic signaling pathway, protein kinase C beta 1 (PKCβ1), may offer a new tool in treating this disease. We appreciate the FDA’s review and look forward to advancing this clinical investigation.”

Z-Endoxifen in Previous Trials

Z-endoxifen has performed well in both phase 1 and phase 2 settings. For instance, in patients who are CDK4/6 inhibitor-naive, Z-endoxifen more than doubled progression-free survival compared with tamoxifen (Soltamox), another widely used endocrine therapy (7.2 vs 2.4 months).²

Further, patients who progressed on tamoxifen and then crossed over to Z-endoxifen achieved partial tumor responses and stable disease. A subset of heavily pretreated patients maintained disease control for more than 2 to 3 years.

In the neoadjuvant setting, the EVANGELINE (NCT05607004)³ trial showed that more than 85% of patients with or without ovarian function suppression achieved suppression of Ki-67 after 4 weeks of treatment.

In the I-SPY2 (NCT01042379)⁴ trial, Z-endoxifen monotherapy at 10 mg once daily met the primary end point of the trial with 95% of patients receiving greater than 75% of planned treatment, with promising rapid activity in reducing 3-week Ki-67 and functional tumor volume at 69% and 30%, respectively. Data from Z-endoxifen combined with abemaciclib (Verzenio) are expected later this year.

In the KARISMA (NCT05068388)⁵ trial, Z-endoxifen at 1 mg reduced mammographic breast density by 19 percentage points (P <.01), compared with a minimal change of 0.27 percentage points in patients who received placebo.

Z-Endoxifen IND Application

In July 2025, Atossa Therapeutics received positive written feedback from the FDA regarding its proposed dose optimization trial for Z-endoxifen, confirming that existing data are sufficient to begin the monotherapy portion (part A). This alignment is a key milestone, as the agency’s guidance on cohort sizes and design refinements ensures the study meets the standards of Project Optimus—an initiative focused on balancing maximum efficacy with minimal toxicity. Atossa plans to evaluate multiple dose levels to satisfy these data-driven requirements.

Beyond monotherapy, the FDA supports the scientific rationale for combining Z-endoxifen with standard-of-care treatments, such as CDK4/6, PI3K, and mTOR inhibitors. This regulatory clarity allows Atossa to refine its upcoming IND application and explore multidrug regimens that could broaden the drug’s utility for patients with advanced ER-positive/HER2-negative metastatic breast cancer.

Importantly, the FDA has deemed the current nonclinical safety package adequate, requiring no further general toxicity or neurotoxicity studies. With the agency also confirming the sufficiency of the cardiac safety monitoring plan—including serial electrocardiograms and QT interval tracking—the preclinical burden is significantly reduced, paving a streamlined path for clinical development.

REFERENCES

1.Atossa Therapeutics receives FDA “Study May Proceed” letter for (Z)-endoxifen investigational new drug application for metastatic breast cancer. News release. Atossa Therapeutics. January 6, 2026. Accessed January 7, 2026. https://tinyurl.com/y65x8meb

2.The science. Atossa Therapeutics. Accessed January 7, 2026. https://tinyurl.com/5n86rsz5

3.(Z)-endoxifen for the treatment of premenopausal women with ER+/HER2- breast cancer (EVANGELINE). ClinicalTrials.gov. Updated October 30, 2025. Accessed January 7, 2026. https://clinicaltrials.gov/study/NCT05607004

4.I-SPY TRIAL: Neoadjuvant and personalized adaptive novel agents to treat breast cancer (I-SPY). ClinicalTrials.gov. Updated August 6, 2025. Accessed January 7, 2026. https://clinicaltrials.gov/study/NCT01042379

5.Effect of oral (Z)-endoxifen in premenopausal women with measurable breast density. ClinicalTrials.gov. Updated April 26, 2024. Accessed January 7, 2026. https://clinicaltrials.gov/study/NCT05068388