Atossa Therapeutics has strategically amended its Phase II EVANGELINE study of (Z)-endoxifen for premenopausal women with breast cancer, reducing the trial size to expedite regulatory submission activities while maintaining scientific rigor. The amendment reflects the company's focus on advancing its lead compound toward New Drug Application (NDA) submission in 2026.
Trial Design Modifications Support Regulatory Strategy
The EVANGELINE study, targeting women with newly diagnosed early-stage Estrogen Receptor-positive (ER+)/Human Epidermal Growth Factor Receptor 2-negative (HER2-) breast cancer, has been restructured from its original 214-participant design to accommodate between 40 and 65 participants. The amended non-registrational design aims to expedite objective outcomes while reducing anticipated future trial costs.
"This amendment is about efficiency, focus and financial discipline," said Steven Quay, Atossa's chairman and CEO. "By streamlining EVANGELINE, we are rationalising study spending and concentrating our strong balance sheet on the NDA-enabling package we plan to advance in 2026, without changing our safety oversight or commitment to rigorous data."
The open-label, single-arm Phase II trial comprises two cohorts with distinct evaluation approaches. Cohort A employs a signal-seeking, two-stage futility design, evaluating the week-4 Ki-67 rate of 10% or lower to facilitate early termination if results are not promising. Cohort B concentrates on the week-24 objective response, utilizing RECIST 1.1 with central review.
Clinical Validation Through I-SPY 2 Results
Recent data from the I-SPY 2 Endocrine Optimization Sub-Study provided strong validation for (Z)-endoxifen's therapeutic potential. Among 20 women with stage II/III ER+, HER2- breast cancer, the primary endpoint was achieved with 95% of subjects completing at least 75% of planned dosing with the low-dose 10 mg monotherapy regimen.
The study demonstrated significant biological activity, with median Ki-67 levels dropping from 10.5% at baseline to 5% by week 3, and 65% of patients achieving Ki-67 ≤10%. This biomarker reduction is clinically meaningful, as the POETIC trial previously demonstrated that women with ER+/HER2- breast cancer whose Ki-67 levels fell to ≤10% after neoadjuvant therapy had a 5-year recurrence rate of 8.4%, compared to 21.5% in those whose Ki-67 remained above 10%.
Imaging results further supported the compound's efficacy, with median functional tumor volume decreasing by 77.7% from baseline to surgery as assessed by MRI, and the longest tumor diameter dropping by 36.8% from baseline to preoperative MRI.
Favorable Safety Profile Across Clinical Programs
Safety data from the I-SPY 2 study showed a favorable profile, with adverse events predominantly Grade 1. Vasomotor symptoms (hot flushes) and fatigue were the most common side effects. 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.
The safety profile builds on extensive clinical experience with (Z)-endoxifen. In over 700 subjects including healthy volunteers and breast cancer patients, doses up to 360 mg/day have been administered with no maximum tolerated dose identified, supporting continued dose-ranging exploration.
Proprietary Formulation Technology
Atossa's development program centers on a proprietary enteric oral formulation of (Z)-endoxifen that bypasses stomach acid, which would otherwise convert the active (Z)-isomer to its inactive (E)-form. This innovation is designed to allow for optimal bioavailability and therapeutic integrity.
(Z)-endoxifen functions as a highly potent Selective Estrogen Receptor Modulator (SERM) with demonstrated ability to inhibit and potentially degrade estrogen receptors. The compound has shown activity even in tumors that have developed resistance to other endocrine therapies. Beyond its anti-estrogenic properties, (Z)-endoxifen also targets protein kinase C beta 1 (PKCβ1), an oncogenic signaling protein, at clinically achievable blood levels.
Expanding Clinical Pipeline and Regulatory Pathway
Patient recruitment in the I-SPY 2 Endocrine Optimization Pilot Analysis, evaluating combination therapy of 40 mg (Z)-endoxifen with Eli Lilly's abemaciclib, continues at a faster rate than anticipated, with 41 patients initiated as of July 29, 2025.
Atossa continues to evaluate (Z)-endoxifen in two additional Phase 2 trials: one in women with ductal carcinoma in situ (DCIS) and another in women with ER+/HER2- breast cancer. The company is prioritizing development for metastatic breast cancer treatment, where novel therapeutic options are urgently needed.
Key upcoming milestones include announcement of the Contract Research Organization selected to execute the metastatic dose-ranging study, disclosure of dose-ranging trial design including patient selection criteria and combination treatment backbone, and targeting IND submission in Q4 2025 in alignment with FDA Project Optimus initiative feedback.
Intellectual Property Portfolio Expansion
Atossa's intellectual property position has been strengthened with the issuance of U.S. Patent No. 12,281,056 in mid-May 2025, containing 58 claims relating to enteric oral formulations of (Z)-endoxifen, including features of improved purity, stability, and bioavailability.
The company holds four additional issued U.S. patents with claims to endoxifen—U.S. Patent Nos. 11,680,036, 12,201,591, 12,275,684, and 12,281,056—with over 200 total claims covering proprietary manufacturing methods, stable crystalline forms, and multiple sustained-release and enteric oral formulations of (Z)-endoxifen. While two patents are currently subject to post-grant challenges, the majority of Atossa's intellectual property remains unaffected.
