Atossa Therapeutics has announced positive topline data from its Phase 2 KARISMA-Endoxifen trial, revealing that (Z)-endoxifen significantly reduces mammographic breast density (MBD) in premenopausal women. The study, conducted at the Karolinska Institute in Stockholm, Sweden, suggests that low doses of (Z)-endoxifen could pave the way for innovative breast cancer prevention strategies.
The ATOS-016R prevention trial randomized healthy women to daily placebo, 1 mg, and 2 mg of (Z)-endoxifen, with 80 women in each arm over six months. Mammographic breast density decrease served as the primary measure of therapy response, comparing measurements at six months or early terminations to baseline density. The results showed no significant differences in age, BMI, or other background factors between the arms.
Key Findings on Breast Density Reduction
The trial demonstrated a relative significant density change of -19.3% and -26.5% for the 1 mg and 2 mg arms, respectively, when compared to the placebo arm. Notably, there was no significant difference observed between the 1 mg and 2 mg arms. These findings are particularly relevant given a 2011 study indicating that women experiencing a breast density decrease of 10% or greater after one year of tamoxifen treatment had a 62% reduction in breast cancer incidence after five years.
Safety and Tolerability
Safety assessments, including hematological tests and vital signs, revealed no significant changes during the trial period. The mean endoxifen plasma concentration reached 5.18 ng/mL in the 1 mg arm and 10.87 ng/mL in the 2 mg arm after one month of therapy, with concentrations remaining stable at three and six months. Discontinuation rates due to drug-related side effects were 4, 5, and 12 in the placebo, 1 mg, and 2 mg arms, respectively. Vasomotor symptoms were not a primary reason for discontinuation; self-assessments using a validated questionnaire indicated only a slight increase in vasomotor symptoms (night sweats, cold sweats, and hot flushes) in the active arms, with a mean increase of 1.4 on a 10-point scale.
Implications for Breast Cancer Prevention
"We are thrilled with the topline results from the KARISMA-Endoxifen Phase 2 trial with (Z)-endoxifen and heartened by the idea that this work may someday lead us to a preventative approach to breast cancer," said Dr. Steven Quay, Chief Executive Officer of Atossa Therapeutics. He further noted the potential of 1 mg of (Z)-endoxifen to significantly reduce breast density, potentially matching or surpassing current therapies without the intolerable side effects, marking a significant advancement for women with dense breasts.
About (Z)-Endoxifen
(Z)-endoxifen is a potent Selective Estrogen Receptor Modulator (SERM) known for its estrogen receptor inhibition and potential to induce estrogen receptor degradation. It has shown efficacy in patients with tumor resistance to hormonal treatments and targets PKCβ1, an oncogenic protein, at clinically achievable blood concentrations. Atossa is developing a proprietary oral formulation of (Z)-endoxifen designed to bypass the stomach, preventing its conversion to the inactive (E)-endoxifen form. The company anticipates presenting detailed results at the San Antonio Breast Cancer Symposium in December, with a full publication in a peer-reviewed journal next year.
