Breakthrough Clinical Results
Atossa Therapeutics has requested a Type C meeting with the FDA to discuss a regulatory strategy for accelerating the development of low-dose (Z)-endoxifen for breast cancer risk reduction. This strategy aims to leverage existing data and published literature to potentially shorten approval timelines and reduce clinical trial costs. (Z)-endoxifen offers advantages over tamoxifen, including consistent therapeutic levels independent of CYP2D6 metabolism and faster achievement of steady-state concentrations. Atossa is also advancing its Phase 2 Project Optimus trial to identify the optimal (Z)-endoxifen dose in metastatic breast cancer, which could further support the risk-reduction indication.
Key Highlights
- Atossa requested a Type C meeting with the FDA to accelerate (Z)-endoxifen development for breast cancer risk reduction.
- (Z)-endoxifen offers advantages over tamoxifen, including consistent efficacy and faster action.
- A successful FDA meeting could significantly shorten approval timelines and reduce costs.
- Atossa is also progressing its Phase 2 Project Optimus trial in metastatic breast cancer.
Incidence and Prevalence
Global Breast Cancer Incidence and Risk Reduction Trends
Recent data from 2024 provides important insights into breast cancer trends globally, with significant variations across regions and populations.
In Türkiye, breast cancer mortality rates increased from 12.26 per 100,000 in 1990 to 12.65 per 100,000 in 2019, with an average annual percentage change (AAPC) of 0.1%. The proportion of deaths attributed to modifiable factors increased by 3% during this period (from 20.4% to 23.1%). High body mass index was the leading contributor to breast cancer mortality, increasing from 3.19% in 1990 to 5.87% in 2019 (AAPC=1.5), followed by high fasting plasma glucose (5.01% to 7.72%; AAPC=1.4).
In China, breast cancer cases increased fourfold between 1990 and 2019, reaching 375,484 cases. Deaths and disability-adjusted life years (DALYs) more than doubled to 96,306 and 2,957,454, respectively. The age-standardized incidence rate (ASIR) increased with an estimated annual percentage change (EAPC) of 2.84 from 1990 to 2019, while the age-standardized mortality rate (ASMR) slightly increased (EAPC=0.06). Projections indicate breast cancer cases and deaths in China will reach 587,700 and 125,600 by 2030, respectively.
Among Asian American women, breast cancer incidence increased for most ethnicities between 1990-2014: Filipina (EAPC=0.96%/year), South Asian (EAPC=1.68%/year), Chinese (EAPC=0.65%/year), Korean (EAPC=2.55%/year), and Vietnamese (EAPC=0.88%/year). For most Asian American ethnicities, ER-positive rates significantly increased while ER-negative rates significantly decreased.
In the United States, 2024 data shows ER-positive cancer incidence increased by 1.75% annually from 2004 to 2009, then slowed to 0.87% annual increase from 2009 to 2019, followed by a 10.2% reduction from 2019 to 2020. ER-negative cancer incidence decreased by 3.13% annually from 2004 to 2012, stabilized from 2012 to 2019 (0.55% annual change), followed by a 6.0% reduction from 2019 to 2020.
The lifetime risk of breast cancer varies by racial/ethnic groups in the US, being lowest in Hispanic women (4.60%) and highest in white women (8.10%). HER2-positive breast cancer varies less by race (1.56-1.91%), while triple-negative breast cancer risk is highest in black women (1.98%) compared to Asians (0.77%), Hispanics (1.04%), and whites (1.25%).
Globally, the quality of breast cancer care improved from 1990 to 2019, with narrowing disparities between countries at different development levels. Universal healthcare coverage is positively associated with national breast cancer care quality across all development levels.
Despite excellent prognosis, stage I and II breast cancers now account for more than 60% of current breast cancer-specific deaths due to their large absolute numbers, with their contribution increasing from 16.2% to 23.1% and from 30.7% to 39.5%, respectively, between 2000 and 2017.
Economic Burden
Economic Burden of Breast Cancer Risk Reduction in USA and Europe
In the USA, Medicare spends approximately $1.08 billion annually on breast cancer screening-related procedures and $1.36 billion on treatment expenditures. For women 75 years or older, annual screening-related expenditures exceed $410 million. The age-standardized screening-related cost varies significantly across regions, ranging from $42 to $107 per beneficiary—a more than 2-fold difference.
Digital screening mammography and computer-aided detection (CAD) account for 65% of the cost difference between high and low-cost regions. Interestingly, women in high screening cost regions are more likely to be diagnosed with early-stage cancer (incidence rate ratio: 1.78), though there is no significant difference in initial cancer treatment costs between highest and lowest screening cost regions ($151 vs $115).
A 2022 study found that AI-based risk prediction followed by no screening for low-risk women is the most cost-effective breast cancer screening strategy for women aged 40-49, with an incremental cost-effectiveness ratio of $23,755 per QALY gained compared to no screening.
The cost of medications has increased substantially. Between 2006 and 2010, the mean annual patient drug cost under Medicare Part D for breast cancer endocrine therapy increased by 19% for tamoxifen, 113% for anastrozole, 89% for exemestane, and 129% for letrozole. By 2010, median annual out-of-pocket costs reached $701 for tamoxifen and up to $3664 for letrozole.
For HER-2 positive metastatic breast cancer, monthly costs vary by disease state, with stable disease costs at $4,158 per month. The last month of life is most expensive at $5,811 per patient per month.
In Europe, a French study of metastatic breast cancer patients found the mean hospital cost per patient was €36,516 with a monthly cost of €3764. Factors affecting costs included hospitalization in palliative care units, trastuzumab treatment, number of recurrence sites, and whether the patient died during the last hospital stay.
The UK has calculated the cost of providing risk-stratification for breast cancer screening at £16.45 for the Tyrer-Cuzick survey approach, £21.82 with Volpara breast-density measurement, and £102.22 when adding SNP testing.
Trastuzumab procurement patterns differ between regions, with Western Europe and the USA reaching proportional use shortly after its early 2000s approval, while Eastern Europe lagged behind, with procurement levels increasing only after its 2006 approval for adjuvant setting.
The COVID-19 pandemic caused a 41% reduction in breast cancer screening coverage, resulting in proportional reductions in direct screening costs. However, chemotherapy treatment costs increased for advanced disease while decreasing for localized disease.
Preventive measures like tamoxifen therapy for breast cancer prevention in Australia costs $38,271 per QALY if the reduction is permanent, or $199,149 per QALY if it merely delays cancer appearance.
Drug used in other indications
(Z)-Endoxifen Clinical Trials Beyond Breast Cancer
Melanoma Clinical Trial
A non-breast cancer clinical trial involving (Z)-endoxifen was conducted in melanoma, as demonstrated in a 2018 publication. This study presented the first demonstration of anti-melanogenic activity of endoxifen both in vitro and in vivo.
Intervention Methodology
In Vitro Studies
- Cell viability assay was used to test the cytotoxic effect
- Endoxifen exhibited greater activity against melanoma cell lines
- Treatment of B16F10 mouse melanoma cell line with 10 μM of endoxifen for 48 h resulted in 93.6% cell death
- Treatment of SK-MEL-5 human melanoma cell line with 10 μM of endoxifen for 48 h resulted in 92.5% cell death
In Vivo Studies
- The anti-melanogenic activity was evaluated in B16F10 cell-bearing C57BL/6 mice, a mouse melanoma model
- Dosing regimen: Orally administered endoxifen at dose levels of 4 and 8 mg/kg body weight/day for 20 consecutive days
- Results showed reduction of metastatic melanoma nodules in the lungs by 26.7% (4 mg/kg) and 82.7% (8 mg/kg)
Safety Profile
- General toxicity was tested in Swiss albino mice
- Endoxifen was found to be a safe and effective anti-melanogenic agent in animal studies
This melanoma trial represents a significant expansion of (Z)-endoxifen's potential therapeutic applications beyond its established role in breast cancer risk reduction.