Atossa Therapeutics, Inc., a clinical‑stage biopharmaceutical company focused on oncology and other areas of high unmet clinical need, has won the Research and Development award in the Precision Endocrine Therapy category in the 2025 Clinical Trials Arena Excellence Awards. The company’s focused development of (Z)-endoxifen, a highly potent selective estrogen receptor modulator/degrader (SERM/D) metabolite of tamoxifen, with additional protein kinase C beta 1 (PKCβ1) inhibition, has reframed a long‑standing prodrug concept into a precision, exposure‑controlled endocrine agent.
Atossa’s program stands out for the way it combines a clear pharmacologic rationale, molecular marker‑driven clinical trial design, adaptive Phase 2 structures, and proactive regulatory engagement into a coherent strategy that spans metastatic treatment, neoadjuvant and adjuvant settings, breast‑cancer risk reduction, and an emerging rare‑disease opportunity in Duchenne Muscular Dystrophy (DMD).
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Precision endocrine platform and clinical differentiation
Atossa’s work in transforming the active metabolite of tamoxifen into a standalone, precision‑engineered drug candidate is a key factor in the recognition. Tamoxifen has a long record of benefit in hormone receptor–positive breast cancer, but its reliance on CYP2D6 metabolism leads to heterogeneous exposure to (Z)-endoxifen. A proportion of patients taking tamoxifen do not achieve therapeutic (Z)-endoxifen levels, and recurrence rates remain notable despite adjuvant therapy, underscoring the limitations of a prodrug approach dependent on variable metabolism.
Atossa’s proprietary enteric‑resistant oral formulation of (Z)-endoxifen is designed to bypass the stomach acid, protect the active (Z)-isomer from conversion to the inactive (E)-form, and importantly, removes CYP2D6 variability by directly delivering the active molecule into the bloodstream. In clinical studies, this formulation has achieved high systemic (Z)-endoxifen concentrations independent of CYP2D6 status, with target concentrations reached within hours and steady state generally within about one week.
This pharmacokinetic control is coupled with a differentiated mechanism of action. (Z)-endoxifen retains the estrogen‑receptor modulation that underpinned tamoxifen’s widespread use since the mid-1970’s, but adds receptor degradation and clinically relevant PKCβ1 inhibition, along with activity against ESR1 mutations and downstream signaling pathways associated with endocrine resistance. In metastatic breast cancer studies, these attributes are reflected in early‑stage clinical data. In CDK4/6 inhibitor–naïve metastatic patients, (Z)-endoxifen achieved a progression‑free survival of 7.2 months compared with 2.4 months for tamoxifen. In addition, patients who had progressed on tamoxifen and then crossed over to (Z)-endoxifen experienced further clinical benefit, including partial responses and prolonged stable disease, with a subset maintaining disease control for more than two to three years.
While these findings come from early‑stage trials, they suggest clinically meaningful differentiation in breast cancer and support continued development of (Z)-endoxifen as an endocrine option across multiple disease settings.
Biomarker‑led development and integrated breast cancer strategy
Atossa’s R&D approach closely links mechanism of action to study design through molecular‑based endpoints, short‑interval readouts, adaptive Phase 2 designs coupled with conventional oncology study endpoints. The EVANGELINE trial in premenopausal women with early‑stage ER+/HER2– breast cancer exemplifies this. EVANGELINE is a single‑arm, open‑label, non‑registrational Phase 2 study in the pre‑surgical setting that uses Ki‑67, a molecular marker of tumor proliferation, as a rapid, objective endpoint. Run‑in data showed that more than 85% of patients (with or without ovarian function suppression) achieved a Week‑4 Ki‑67 level of ≤10%, a rate higher than published comparators in similar window‑of‑opportunity designs with tamoxifen or aromatase inhibitors plus ovarian function suppression. The company has emphasized that no efficacy conclusions can yet be drawn from this ongoing study and that the data remain exploratory.
In October 2025, Atossa amended EVANGELINE to streamline the design and align it with its 2025–2026 operating plan. Planned enrollment was reduced from 214 to 40–65 patients, and a two‑stage futility rule was introduced for Cohort A (patients with initial Ki‑67 >10%), allowing early stopping based on Week‑4 Ki‑67 outcomes. Cohort B (initial Ki‑67 <10%) is designed to estimate Week‑24 objective responses by central RECIST 1.1 review. Safety monitoring and Data Safety Monitoring Committee oversight remain unchanged. This amendment aims to preserve decision‑relevant data while reducing projected future costs and enabling earlier go/no‑go decisions—an important feature for capital‑efficient development of a single lead asset.
Atossa’s participation in the I‑SPY2 program reinforces this biomarker‑focused methodology. In the I‑SPY2 sub‑study, (Z)-endoxifen monotherapy at 10mg once daily met its primary endpoint, with 95% of patients receiving more than 75% of the planned treatment and showed rapid reductions in three‑week Ki‑67 and functional tumor volume. These results align the early biological effects seen in neoadjuvant settings with the pharmacologic profile observed in metastatic disease.
The same logic underpins an integrated development plan that spans the full continuum of ER‑positive breast cancer. In metastatic disease, Atossa is prioritizing a Phase 2 program aligned with the FDA’s Project Optimus initiative to define optimal dosing via exposure–response analyses. In parallel, it is advancing neoadjuvant studies such as EVANGELINE and I‑SPY2, as well as Phase 2 studies in ductal carcinoma in situ (DCIS) and ER+/HER2– breast cancer that explore monotherapy in DCIS and low‑risk disease and combination regimens, including pairing (Z)-endoxifen with abemaciclib, in higher‑risk cancers. Additionally, the Phase 2 KARISMA trial has shown that a 1 mg dose of (Z)-endoxifen reduced mammographic breast density—a recognized risk factor for breast cancer—by 19 percentage points (p<0.01), compared with a 0.27‑percentage‑point change in the placebo group. Together, these studies position (Z)-endoxifen as a single molecule being evaluated across risk reduction, neoadjuvant, adjuvant, and metastatic settings within a unified mechanistic and pharmacokinetic framework.
Regulatory engagement is tightly woven into this strategy. In metastatic breast cancer, the Phase 2 metastatic trial is designed to meet the FDA’s expectations on exposure–response characterization and dose optimization at an early stage (Project Optimus). The company has engaged the FDA in discussions pertaining to the regulatory pathways for advancing these programs. This followed an external review of the company’s data and the broader literature by regulatory experts. According to Atossa’s December 4 update, the outcome of Type C meeting with the FDA, which was held on November 17, resulted in feedback that is now helping inform and align the Company’s overall clinical development strategy for (Z)-endoxifen across multiple indications. The FDA’s guidance addressed potential expedited pathways, endpoint strategy, and clinical trial design considerations spanning metastatic disease, neoadjuvant therapy, and risk-reduction settings, offering clarity on how a coordinated development approach could support future regulatory review. Combined with the EVANGELINE amendment and Atossa’s focus on clinical trial design and data generation, these measures reflect a deliberate effort to link scientific, clinical, financial, and regulatory considerations into a single, time efficient development plan for (Z)-endoxifen.
Extending precision endocrine logic into Duchenne Muscular Dystrophy
Beyond oncology, Atossa is investigating how the pharmacology of (Z)-endoxifen might be applied to Duchenne Muscular Dystrophy and Duchenne carrier–associated pathologies. Prior clinical experience with tamoxifen in DMD suggested safety and encouraging trends before trial termination during the COVID‑19 pandemic, prompting interest in more potent and exposure‑reliable metabolites.
A recently published peer‑reviewed hypothesis article examines the potential role of (Z)-endoxifen in DMD. The paper outlines how (Z)-endoxifen’s direct estrogen‑receptor modulation, allosteric PKC inhibition (notably PKCβ1), and effects along AKT/mTOR and NF‑κB signaling could be relevant to downstream drivers of DMD pathology, including inflammation, fibrosis, calcium dysregulation, mitochondrial dysfunction, lipid abnormalities, and cardiomyopathy. The publication also highlights the advantage of more consistent therapeutic exposure with (Z)-endoxifen compared with tamoxifen, given its independence from CYP2D6 variability. As further evidence of the importance of addressing unmet needs associated with DMD, Atossa announced on December 11, 2025, that they received a Rare Pediatric Disease designation from the FDA, which will provide further advantages and opportunities as they advance this program clinically and through the regulatory pathways.
In addition, Atossa has submitted a second manuscript, currently under review, entitled, “(Z)-Endoxifen as a Modulator of Utrophin Pathways in Duchenne Muscular Dystrophy.” This work focuses on utrophin, a structural and functional analog of dystrophin that can help stabilize the sarcolemma and mitigate muscle fiber damage. The company has highlighted the potential relevance of (Z)-endoxifen in symptomatic female Duchenne carriers, an under‑recognized population in which a subset may experience skeletal‑muscle symptoms or develop dilated cardiomyopathy, through an invited presentation titled “Endoxifen: A Potential Novel Therapy for Duchenne Carrier‑Associated Pathologies” delivered at the 2nd International Conference on Women’s Health, Reproduction & Obstetrics.
Atossa has indicated that it intends to use the published framework to guide prioritized preclinical validation and the design of fit‑for‑purpose clinical studies in DMD and carrier populations, with emphasis on safety, pharmacokinetics, pharmacodynamics, and functional endpoints relevant to skeletal and cardiac muscle. While this work is at an earlier stage than the breast‑cancer program, it shows how the same endocrine and PKC‑focused pharmacology underlying (Z)-endoxifen’s oncology development can be systematically evaluated in a rare neuromuscular disease setting. This combination of mechanistic rigor, program integration, and regulatory planning underpins Atossa’s recognition in the Research and Development – Precision Endocrine Therapy category this year.
“We are honored to receive the Clinical Trials Arena R&D Excellence Award for Precision Endocrine Therapy, which recognizes the innovative work our team has done with (Z)-endoxifen. The recent FDA Type C meeting further underscores our commitment to a coordinated, science-driven strategy, providing guidance that helps us align our clinical development across metastatic, neoadjuvant, adjuvant, and risk-reduction settings. Together, these milestones reflect our goal of advancing (Z)-endoxifen efficiently while maintaining the highest standards of scientific and regulatory rigor.”
– Dr Steven Quay, M.D., Ph.D., President, Atossa Therapeutics
Company Profile
Atossa Therapeutics, Inc. (Nasdaq: ATOS) is a clinical-stage biopharmaceutical company developing novel therapies in oncology and other areas of high unmet clinical need, including (Z)-endoxifen, to improve outcomes for patients across the breast cancer continuum of care.
Links:
Website: https://atossatherapeutics.com/
