Atossa Therapeutics has outlined a framework for a potentially groundbreaking Phase 3 clinical study aimed at reducing interval breast cancer in high-risk women. The proposed trial, named SMART 2.0, was presented at the American Association for Cancer Research (AACR) Annual Meeting 2025 and would investigate the company's proprietary oral (Z)-endoxifen as a preventive therapy.
Interval breast cancers, which are diagnosed between regular mammography screenings, typically present as more aggressive and challenging to treat compared to screen-detected cancers. Mammographic density has been identified as a critical and modifiable risk factor that can complicate early detection of breast tumors.
"The SMART 2.0 study proposal represents a significant step forward for the advancement of breast cancer prevention," said Steven C. Quay, CEO of Atossa Therapeutics. "By targeting mammographic density with Z-endoxifen, we hope to establish a safer, more effective preventive therapy for women at high risk."
Novel Approach to Breast Cancer Prevention
The SMART 2.0 trial would leverage an AI Risk model to identify and randomize high-risk participants into treatment and placebo groups. The primary endpoint would measure the relative reduction in interval breast cancer incidence and tolerability compared to placebo over a two-year period.
This approach builds on promising results from Atossa's Phase 2 KARISMA trial, where low-dose (1mg) (Z)-endoxifen reduced mammographic density by nearly 20 percent at six months. Importantly, systemic side effects were not statistically different from placebo—a critical advantage over existing preventive options.
(Z)-Endoxifen: A Potent SERM with Multiple Mechanisms
(Z)-endoxifen is one of the most potent Selective Estrogen Receptor Modulators (SERMs) for estrogen receptor inhibition and may cause estrogen receptor degradation. The compound has demonstrated efficacy in patients with tumor resistance to other hormonal treatments.
Beyond its anti-estrogen effects, (Z)-endoxifen targets PKCβ1, a known oncogenic protein, at clinically attainable blood concentrations. The drug appears to deliver similar or even greater bone agonistic effects while resulting in minimal endometrial proliferative effects compared with standard treatments like tamoxifen.
Atossa's proprietary oral formulation is specially encapsulated to bypass the stomach, as acidic conditions can convert a significant proportion of the active (Z)-endoxifen to its inactive (E) form.
Addressing an Unmet Medical Need
Previous research indicates that while tamoxifen effectively reduces breast density and potentially enhances mammogram sensitivity, its adverse effects limit widespread adoption as a preventive therapy.
The SMART 2.0 study aims to provide pivotal data required for regulatory approval of (Z)-endoxifen as a preventative treatment option. If successful, this could represent a significant advancement in breast cancer prevention strategies, particularly for women with high mammographic density who face increased cancer risk.
Broader Development Program
(Z)-endoxifen is currently being studied for both treatment and prevention of breast cancer. Atossa's development program includes investigations across the breast cancer spectrum, including prevention, neoadjuvant, adjuvant, and metastatic settings.
Earlier this year, the company announced a program specifically focused on metastatic breast cancer, highlighting the compound's versatility and potential broad clinical utility.
As a Nasdaq-listed clinical-stage biopharmaceutical company (ATOS), Atossa Therapeutics continues to advance its clinical research programs with the goal of transforming breast cancer treatment through innovative science and patient-focused solutions.
