Atossa Therapeutics reported promising results from its Phase 2 Endocrine Optimization Pilot (EOP) sub-study within the I-SPY 2 TRIAL, showing that low-dose oral (Z)-endoxifen significantly reduced tumor size in women with estrogen receptor-positive (ER+), HER2-negative breast cancer.
The study evaluated a 10 mg daily dose of (Z)-endoxifen as a neoadjuvant treatment in 20 women with stage II/III breast cancer. Results showed a substantial 77.7% decrease in median functional tumor volume (FTV) from baseline to surgery, with measurements changing from 9.0 cc to 1.2 cc. Additionally, the longest tumor diameter was reduced by 36.8% from baseline to preoperative MRI.
Strong Feasibility and Early Anti-Proliferative Effects
The trial surpassed its primary feasibility endpoint, with 95% of participants (19/20) completing at least 75% of the planned dosing regimen, exceeding the predefined 75% threshold.
Early anti-proliferative activity was evident, as median Ki-67 levels—a marker of cell proliferation—fell from 10.5% at baseline to 5% by Week 3, prior to ovarian suppression. Notably, 65% of patients achieved Ki-67 levels ≤10% at that time point, and this suppression was maintained through surgery.
"These results show that even at a low capsule strength (Z)-endoxifen is bioactive, producing rapid Ki-67 suppression and meaningful tumor shrinkage, while remaining highly tolerable," said Steven Quay, M.D., Ph.D., President and Chief Executive Officer of Atossa. "The study strengthens our scientific hypothesis that dual targeting of ERα and PKCβ1 is key to inducing a pathological response."
Safety Profile and Pathologic Findings
The drug demonstrated a favorable safety profile, with adverse events predominantly classified as Grade 1. The most common side effects were vasomotor symptoms (hot flushes) and fatigue. Only three Grade 3 events occurred in a single patient—two skin infections and one post-procedural infection—all deemed unrelated to the study drug. No Grade 4 or Grade 5 events were reported.
Despite the significant tumor shrinkage, no participants achieved a pathologic complete response (pCR), and residual cancer burden (RCB) classes skewed toward RCB-II/III, indicating moderate to extensive residual disease.
This outcome was anticipated based on earlier studies showing that significant pathologic clearance typically requires higher systemic exposures to (Z)-endoxifen (>500 ng/mL) to enable inhibition of PKCβ1 in addition to ERα. The 10 mg dose in this pilot was intentionally selected to establish tolerability and early biologic activity in the endocrine-naïve setting.
Mechanism of Action and Future Directions
(Z)-endoxifen is a highly potent Selective Estrogen Receptor Modulator (SERM) with demonstrated ability to inhibit—and potentially degrade—estrogen receptors. Beyond its anti-estrogenic properties, it also targets protein kinase C beta 1 (PKCβ1), an oncogenic signaling protein, at clinically achievable blood levels.
Atossa has developed a proprietary oral formulation of (Z)-endoxifen that is enteric-coated to bypass stomach acid, which would otherwise convert the active (Z)-isomer to its inactive (E)-form. This innovation ensures optimal bioavailability and therapeutic integrity.
The company is now actively enrolling participants into an additional I-SPY 2 cohort testing (Z)-endoxifen at a higher 40 mg daily dose and in combination with the CDK4/6 inhibitor abemaciclib, with and without ovarian function suppression. Top-line data from these arms are expected beginning in 2026.
"Importantly, it paves the way for our ongoing I-SPY 2 cohorts evaluating higher, potentially PKCβ1-engaging doses of (Z)-endoxifen alone and in combination with the CDK4/6 inhibitor abemaciclib, where we aim to translate early biomarker gains into deeper pathologic responses," Quay added.
Current Development Program
Atossa is prioritizing the development of (Z)-endoxifen for the treatment of metastatic breast cancer, where novel therapeutic options are urgently needed. The compound is currently being evaluated in three Phase 2 trials: one in women with ductal carcinoma in situ (DCIS) and two in women with ER+/HER2- breast cancer, including the EVANGELINE trial and the combination I-SPY study.
The company's (Z)-endoxifen program is supported by a growing global intellectual property portfolio, including three recently issued U.S. patents and numerous pending applications worldwide.
Clinical Implications
Breast cancer remains the most common cancer in women worldwide, with ER+ subtypes accounting for approximately 70% of cases. While endocrine therapies have improved outcomes, resistance remains a significant challenge, highlighting the need for novel approaches like (Z)-endoxifen that can potentially overcome resistance mechanisms.
The promising results from this study suggest that (Z)-endoxifen could potentially address important limitations of current standard-of-care therapies. Notably, the drug appears to deliver comparable or superior bone-protective effects relative to tamoxifen, while exhibiting minimal or no endometrial proliferative activity—addressing key safety concerns with existing treatments.
As Atossa continues to advance its clinical program with higher doses and combination approaches, (Z)-endoxifen may emerge as an important new option in the breast cancer treatment landscape, particularly for patients who have developed resistance to current endocrine therapies.
