ATOS

ATOSSA THERAPEUTICS, INC.

NASDAQ · HEALTH CARE · PHARMACEUTICAL PREPARATIONS

2.72

+0.19 +7.51%

USD · close Oct 22

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MKT CAP $27.1MP/E —DIV YIELD —FCF YIELD -131.83%REV TTM —NET INCOME −$37.7MNET CASH $26.1M52W 1.75 – 14.10SEC XBRL · TTM TO Invalid Date

How ATOS rewrote its risk factors

10-K ITEM 1A · FY2024 → FY2025

Text kept

55%

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words, now 35,206

New in FY2025

We make available, free of charge through our website, our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other periodic SEC reports, along with amendments to all of those reports, as soon as reasonably practicable after we file the reports with the SEC.
BUSINESS Overview We are a clinical-stage biopharmaceutical company developing proprietary innovative medicines in areas of significant unmet medical need in oncology, with a focus on breast cancer and other breast conditions.
Our lead drug candidate is oral (Z)-endoxifen, a selective estrogen receptor modulator (SERM)/ selective estrogen receptor degrader (SERM/D) currently in Phase 2 clinical development.
The Company is evaluating potential indications for (Z)-endoxifen based on its pharmacologic profile, including its potential for both reducing the risk of and for the treatment of breast cancer, as well as in other therapeutic areas.
We have been granted U.S. and international patents covering our proprietary (Z)-endoxifen, and we have numerous applications pending in the U.S. and in other major countries.
We expect to have patent protection covering our proprietary (Z)-endoxifen through at least November 17, 2038.
Our business strategy is to advance our programs through clinical studies, including with potential partners, and opportunistically add programs in areas of high unmet medical need through acquisition, minority investment, collaboration, or internal development.
(Z)-endoxifen is the most active metabolite of Tamoxifen and is substantially more potent as an estrogen receptor antagonist than Tamoxifen and other approved SERMs.
Unlike Tamoxifen, which requires metabolic activation through CYP2D6 and other liver enzymes, (Z)-endoxifen does not require first-pass metabolism to achieve therapeutic concentrations.
As a result, its activity is not dependent on patient-specific metabolic variability.
(Z)-endoxifen is a small-molecule oral agent designed to directly inhibit estrogen receptor signaling, induce estrogen receptor degradation, and promote apoptosis in estrogen receptor positive (ER+) breast cancer cells.
Preclinical and clinical data suggest that (Z)-endoxifen may inhibit clinically relevant ESR1 mutations associated with resistance to aromatase inhibitors and may also inhibit protein kinase C beta one (PKCβ1), resulting in downregulation of the AKT signaling pathway.
We are evaluating (Z)-endoxifen across multiple settings within the ER+/human epidermal growth factor receptor 2 negative (HER2-) breast cancer treatment continuum, including neoadjuvant, adjuvant and breast density reduction indications.
In an ongoing neoadjuvant clinical study, (Z)-endoxifen has demonstrated early signs of anti-tumor activity.
Reported results include one complete response and multiple partial responses, as well as substantial reductions in Ki-67 proliferation across dose levels.
Tumor shrinkage was observed by MRI imaging, which is atypical for endocrine therapies that are generally cytostatic.
We are also supporting multiple collaborative and investigator-sponsored clinical studies evaluating (Z)-endoxifen in additional breast cancer settings.
These studies are not fully funded by us and are intended to further characterize clinical activity, optimize endocrine therapy strategies, and inform future regulatory pathways.
Based on its mechanism of action, we are exploring the potential application of (Z)-endoxifen beyond breast cancer, including gynecological cancers, endocrine resistance driven by ESR1 mutations, as well as applications in other rare disease indications, including Duchenne Muscular Dystrophy (DMD), women carriers of DMD, and McCune-Albright Syndrome (MAS) in girls.
In preclinical models of DMD, (Z)-endoxifen demonstrated muscle-protective, anti-inflammatory, and anti-fibrotic effects.
We believe similar efficacy could potentially apply to women carriers of DMD.
For MAS, we believe (Z)-endoxifen could potentially be an effective hormone blocker, significantly reducing the effects of early onset puberty in young girls.
We have developed a proprietary manufacturing process for (Z)-endoxifen, including defined processes for the active pharmaceutical ingredient and drug product.
The drug product is available in multiple dosage strengths and is supported by qualified suppliers and manufacturing redundancies.
Summary of Leading Oncology Programs (Z)-endoxifen is currently being investigated in four Phase 2 trials: Karisma-(Z)-endoxifen: We are developing our proprietary oral (Z)-endoxifen as a potential therapy to help reduce mammographic breast density (MBD).
In December 2021, we initiated the Karisma-(Z)-endoxifen study, a Phase 2, randomized, double-blind, placebo-controlled, dose-response study evaluating the effect of low-dose (Z)-endoxifen on MBD in healthy premenopausal women with measurable MBD.
The study was conducted in Stockholm, Sweden and enrolled 240 participants who were randomized to receive daily oral dosing for six months of either placebo, 1 mg of (Z)-endoxifen, or 2 mg of (Z)-endoxifen.
The primary endpoint was dose-response reduction in MBD.
Secondary endpoints included safety and tolerability, and an exploratory endpoint assessed durability of MBD changes over 24 months.
The study fully enrolled in November 2023 and concluded in June 2024 with database lock in September 2024.
The follow up 24-month mammographic record review of participants is expected to conclude by the end of the first quarter in 2026.
Durability data is expected to be received at the end of Q2.
The initial study data demonstrated that low-dose (Z)-endoxifen significantly reduced MBD compared to placebo.
The 1 mg dose showed a mean MBD reduction of 17.3% (p<0.01) and the 2 mg dose showed a mean reduction of 23.5% (p<0.01), compared to a 0.27% change in the placebo group.
Mean plasma concentrations were 4.8 ng/mL and 9.7 ng/mL in the 1 mg and 2 mg dose groups, respectively, indicating that substantial MBD reductions were achieved at relatively low systemic exposure.
(Z)-endoxifen was generally well tolerated.
No meaningful differences in adverse events were observed between the 1 mg dose group and placebo.
The 2 mg dose group experienced higher rates of certain adverse events, including hot flashes, night sweats, and vaginal discharge.
We expect to report top-line data from the Karisma-(Z)-endoxifen study in the first half of 2026.
Further development will depend on regulatory guidance, study outcomes, and available resources.

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Gone since FY2024

We make available, free of charge through our website or upon written request, our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other periodic SEC reports, along with amendments to all of those reports, as soon as reasonably practicable after we file the reports with the SEC.
BUSINESS Overview We are a clinical-stage biopharmaceutical company developing proprietary innovative medicines in areas of significant unmet medical need in oncology with a focus on women’s breast cancer and other breast conditions.
Our lead drug candidate under development is oral (Z)-endoxifen, which we are developing for both the prevention and treatment of breast cancer and other therapeutic areas.
Our business strategy is to advance our programs through clinical studies, including potentially with partners, and opportunistically add programs in areas of high unmet medical need through acquisition, minority investment, collaboration or internal development.
(Z)-endoxifen is an active metabolite of tamoxifen, which is an FDA-approved drug to treat and prevent breast cancer.
Tamoxifen is a "pro-drug," in that it must be metabolized into active components or metabolites to be effective.
Despite the success of tamoxifen in treating Estrogen Receptor Positive (ER+) breast cancer, its systemic side effects have led to generally low acceptance as a therapy to reduce the risk of breast cancer.
These systemic side effects relate to estrogen agonist activity on the endometrium and the activation of coagulation pathways, leading to an increased risk of uterine events and thromboembolism.
Hot flashes and vaginal symptoms are additional barriers to tamoxifen being accepted in the prevention setting.
Other limiting aspects of tamoxifen are that some people lack liver enzymes to adequately metabolize it and it can take a long time for many patients to reach therapeutic levels.
Up to 50% of breast cancer survivors who take tamoxifen do not achieve therapeutic (Z)-endoxifen levels (meaning they are “refractory”) for a number of reasons, including that they, due to their genotype, do not have the requisite liver enzymes.
We believe our proprietary oral (Z)-endoxifen, in part because it is not a pro-drug and does not need to be metabolized by the liver, may overcome some of the shortcomings of tamoxifen.
(Z)-endoxifen is a proprietary, novel Selective Estrogen Receptor Modulator (SERM), which is a class of drug that blocks estrogen from connecting with breast cancer cells, with the intent of keeping the cells from multiplying.
We are developing oral (Z)-endoxifen for the potential prevention and treatment of breast cancer.
We have completed four Phase 1 clinical studies (including a study in men) and two Phase 2 clinical studies with our proprietary (Z)-endoxifen (including oral and topical formulations).
We have also developed clinical manufacturing capabilities through qualified third-parties.
Summary of Leading Programs (Z)-endoxifen is currently being investigated in four Phase 2 trials: EVANGELINE : EVANGELINE is a Phase 2 randomized study evaluating (Z)-endoxifen as neoadjuvant therapy for premenopausal women with primary ER+, HER2– breast cancer.
The trial will enroll approximately 190 patients across up to 25 U.S. sites and is divided into two parts: Part 1: Pharmacokinetic (PK) Run-In Cohort: A 40 mg/day cohort was opened in February 2023 to assess if plasma steady state concentrations (Css) of 500 to 1000 ng/mL, which is required for optimal PKC-β inhibition, could be achieved.
Subsequently, an 80 mg/day PK cohort was initiated and fully enrolled in July 2024.
Data from both the 40 mg and 80 mg cohorts, which included 12-week and 24-week Magnetic Resonance Imaging (MRI) and safety assessments, showed that no patients in the 40 mg cohort achieved the target plasma Css.
In the 80 mg cohort, approximately 50% of patients receiving (Z)-endoxifen with Ovarian Function Suppression (OFS or goserelin) and 38% of patients receiving (Z)-endoxifen alone reached the target plasma Css, with an average plasma Css of 484 ng/mL.
We believe that targeting PKC-β may further enhance (Z)-endoxifen's antitumor activity.
As part of a previously amended protocol, tumor Css levels were assessed in the 80 mg cohort and were found to be more than double the plasma levels, exceeding 500 ng/g in 90% of patients.
Substantial tumor suppression was also observed, with 85% of patients exhibiting a 4-week Ki-67 response (≤10%), regardless of ovarian function suppression.
(Z)-endoxifen was well tolerated overall.
No significant Grade 3 or 4 toxicities were observed, although four gynecologic events were reported in the 80 mg group, including one Grade 3 hemorrhagic ovarian cyst.
In January 2025, based on an analysis of Part 1 of the study, which included the PK, efficacy and safety data, we further revised the study protocol to focus on the 40 mg per day dose, a dose we believe to be sufficient to achieve tumor Css levels >500 ng/g for effective PKC-β1 targeting.
Part 2: The Treatment Cohort: This cohort is expected to be initiated in the first half of 2025 and compares two treatment arms: Part 2a, which assesses (Z)-endoxifen plus goserelin for patients with baseline Ki-67 >10%, and Part 2b, which assesses (Z)-endoxifen on its own for patients with baseline Ki-67 ≤10%.
The primary objective of Part 2a is to determine if the endocrine sensitive disease rate (ESDR), which is defined as the percentage of patients with Ki-67 ≤10% after 4 weeks of treatment in patients given (Z)-endoxifen plus goserelin is non-inferior to the ESDR in patients given exemestane plus goserelin, in patients with baseline Ki-67 ≥10%.
The primary objective of Part 2b is to evaluate the 24-week ESDR in patients with baseline Ki-67 ≤10%.
Secondary endpoints for both cohorts include pathologic complete response (pCR) at surgery, the Preoperative Endocrine Prognostic Index (PEPI), residual cancer burden (class 0–1), as well as safety and laboratory assessments.
Karisma-(Z)-endoxifen: Karisma-(Z)-endoxifen is a Phase 2 study of our proprietary oral (Z)-endoxifen in healthy premenopausal women with measurable mammographic breast density (MBD).
In November 2024, the Karisma-(Z)-Endoxifen study reported data which showed the potential of low-dose (Z)-endoxifen to significantly reduce MBD, a key risk factor for breast cancer, while showing a favorable safety profile.
The randomized, double-blind, placebo-controlled study enrolled 240 premenopausal women aged 40-55, randomized to one of three arms: placebo, 1 mg, or 2 mg of daily oral (Z)-endoxifen for six months.
The study aimed to evaluate reductions in MBD and assess safety and tolerability.
Mammograms were conducted to measure the reduction in breast density over the treatment period and a final mammogram will be conducted at 24 months to assess the durability of density changes.
Results showed that the 1 mg dose of (Z)-endoxifen reduced MBD by 17.3% (p<0.01), while the 2 mg dose achieved a reduction of 23.5% (p<0.01), compared to a minimal change in the placebo group of 0.27 percentage points.
Plasma concentrations for (Z)-endoxifen were measured at 4.8 ng/mL and 9.7 ng/mL for the 1 mg and 2 mg arms, respectively, which showed the effectiveness of the lower dose in achieving significant reductions.
Importantly, no significant differences in adverse events were observed between the 1 mg dose and the placebo.
The 2 mg dose was associated with higher rates of hot flashes, night sweats and vaginal discharge.

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Sentence-level comparison of Item 1A in the two most recent 10-Ks (FY2024 ↗, FY2025 ↗). A reworded sentence counts as one dropped and one added, so heavy edits read as low “kept”. Headings and page furniture are stripped; nothing is summarised by a model.

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