Clinical Trials

Risk Reduction

Targeting a Validated Breast-Cancer Risk Marker

Mammographic breast density (MBD) is an independent risk factor for breast cancer and is now included in U.S. mammography reporting. Endocrine interventions can reduce breast density, making MBD a useful biomarker for studying biological effects relevant to risk reduction.

KARISMA-(Z)-endoxifen was a randomized, double-blind, placebo-controlled Phase 2 study in premenopausal women with measurable breast density. In the study, low-dose (Z)-endoxifen produced a substantial reduction in mammographic breast density compared with placebo, with encouraging tolerability.

These findings support further study of low-dose (Z)-endoxifen as a potential risk-reduction strategy. Reduction in breast density is a biomarker; (Z)-endoxifen has not been established to prevent breast cancer.

KARISMA Trial:
A 1 mg dose of (Z)-endoxifen reduced mammographic breast density by 19 percentage points compared to minimal change in placebo.

Low-Dose Activity:
Clinically meaningful biological effects were observed at low plasma concentrations, with no significant increase in adverse events versus placebo.

These findings highlight the potential for (Z)-endoxifen to impact early disease biology while maintaining tolerability.

Metastatic Breast Cancer

Clinical Evidence in Advanced Disease

Earlier clinical studies of (Z)-endoxifen in advanced ER-positive breast cancer demonstrated anti-estrogen activity and signals of clinical benefit, including in patients previously treated with endocrine therapy. In a randomized study conducted by the National Cancer Institute, (Z)-endoxifen was evaluated against tamoxifen in women with metastatic breast cancer.

Improved Progression-Free Survival:
In front-line, CDK4/6 inhibitor–naïve patients, (Z)-endoxifen more than doubled median PFS compared to tamoxifen (7.2 vs. 2.4 months).

Activity After Tamoxifen Progression:
Patients who crossed over following tamoxifen progression experienced meaningful outcomes, including partial responses and prolonged stable disease. Some maintained disease control beyond 2–3 years.

(Z)-endoxifen is designed to overcome key limitations of current therapies, with the potential to extend the benefits of endocrine treatment to more patients.

Atossa Therapeutics is working with the U.S. Food and Drug Administration to explore streamlined development pathways for other earlier-stage indications.

These data contribute to the clinical evidence supporting (Z)-endoxifen’s activity and help inform development in other breast-cancer settings. Atossa has paused investment in a dedicated metastatic breast cancer development program while prioritizing other oncology and rare-disease opportunities.

Neoadjuvant Setting

Studying Endocrine Therapy Before Surgery

Atossa and academic collaborators are evaluating (Z)-endoxifen before surgery in women with ER-positive/HER2-negative breast cancer.

EVANGELINE:
This study is evaluating (Z)-endoxifen in the neoadjuvant setting and has generated encouraging early biomarker and response data. Initial results demonstrate promising activity, including complete and partial responses. Ki-67 response rates (≤10%) exceeded 85% across dose levels.

I-SPY 2 Endocrine Optimization Pilot:
In the monotherapy cohort, the study met its prespecified treatment-completion endpoint, with 19 of 20 participants receiving at least 75% of planned therapy. The study also showed early biological activity, including reductions in Ki-67 and functional tumor volume.

Atossa is also supporting combination studies designed to determine how (Z)-endoxifen may be integrated with other endocrine and targeted therapies.

Adjuvant Setting

A Potential Future Role After Surgery

Adjuvant endocrine therapy can substantially reduce recurrence risk in ER-positive early breast cancer, but long treatment duration, side effects, pharmacologic variability, and treatment discontinuation remain important challenges.

Atossa believes (Z)-endoxifen’s direct delivery of the active compound and the tolerability observed in studies to date support further evaluation in earlier-stage disease. The company is exploring development strategies and regulatory pathways that could define an appropriate role for (Z)-endoxifen after surgery.