Novel SERM Reduces Mammographic Breast Density in Premenopausal Population

Investigators anticipate presenting detailed findings from the KARISMA-Endoxifen trial at the 2024 San Antonio Breast Cancer Symposium (SABCS). Additionally, these results will be fully published in a peer-reviewed journal in 2025.

Low doses of (Z)-endoxifen, an investigational selective estrogen receptor modulator (SERM), significantly decreased mammographic breast density (MBD) and demonstrated tolerability among premenopausal individuals, according to a news release on findings from the phase 2 KARISMA-Endoxifen study.¹

Data showed a density change of –19.3% with (Z)-endoxifen at 1 mg and –26.5% at 2 mg compared with placebo. Investigators reported no significant differences when administering the agent at 1 mg or 2 mg. According to the news release, findings from a study published in 2011 showed that those with a breast density decrease of 10% or higher following treatment with tamoxifen for 1 year experienced a reduction in breast cancer after 5 years by 62%.²

Treatment yielded no changes in hematological safety tests or vital signs during the trial period. The mean endoxifen plasma concentration when (Z)-endoxifen was given at 1 mg and 2 mg, respectively, was 5.18 ng/mL and 10.87 ng/mL after 1 month of treatment. In each respective arm, 5 and 12 patients discontinued treatment due to adverse effects (AEs) that were related to the agent compared with 4 patients in the placebo arm. No patients discontinued study therapy due to vasomotor symptoms.

Individuals self-assessed symptoms using a validated 36-question survey, which included a five-graded Likert scale. Only vasomotor symptoms such as night and cold sweats and hot flushes increased by a mean of 1.4 points on a 10-point scale.

Investigators anticipate presenting detailed findings from the KARISMA-Endoxifen trial at the 2024 San Antonio Breast Cancer Symposium (SABCS). Additionally, these results will be fully published in a peer-reviewed journal in 2025.

“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,” Steven Quay, MD, PhD, chief executive officer at Atossa Therapeutics, the developers of (Z)-endoxifen, stated in the news release.¹ “Although further analysis of this study is required, the potential that 1 mg of (Z)-endoxifen may significantly reduce breast density as well as, if not better than, currently available therapies, potentially without many of the intolerable [AEs], is extremely encouraging and a significant step toward a solution for millions of women with dense breasts.”

Designed to inhibit and potentially degrade estrogen receptors, (Z)-endoxifen has demonstrated the capability of targeting the oncogenic protein PKCβ1 at clinically attainable blood concentrations. Compared with standard therapy options such as tamoxifen, developers hypothesize that (Z)-endoxifen may yield similar or improved bone agnostic effects while potentially reducing endometrial proliferative effects.

Investigators of the KARISMA-Endoxifen trial recruited healthy women who were randomly assigned to receive (Z)-endoxifen at 1 mg or 2 mg or matched placebo. Each study arm included 80 individuals; treatment lasted for 6 months.

One of the trial’s key end points was MBD reduction, which investigators used as a proxy for therapy response. Six-month measurements or early terminations were compared with baseline density. Investigators reported no significant differences in age, body mass index, or other background factors across treatment arms.

In November 2023, developers announced that the phase 2 KARISMA-Endoxifen trial reached full patient enrollment.³

“Many of the risk factors for breast cancer, including breast density, are known, which means treating at-risk patient populations before the disease develops could significantly lower incidence rates,” principal trial investigator Per Hall, MD, a professor of Epidemiology at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet in Stockholm, Sweden, stated at the time the trial reached full enrollment.³ “I expect the medical community and government entities to increase their focus on breast cancer prevention, which should expedite the development and availability of novel treatments like (Z)-endoxifen.”

References

1. Atossa Therapeutics reports positive KARISMA-Endoxifen trial results. News release. Atossa Therapeutics, Inc. November 4, 2024. Accessed November 4, 2024. https://tinyurl.com/3d38zva9
2. Cuzick J, Warwick J, Pinney E, et al. Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: a nested case-control study. J Natl Cancer Inst. 2011;103(9):744-752. doi:10.1093/jnci/djr079.
3. Atossa Therapeutics announces full enrollment of phase 2 Karisma-Endoxifen clinical trial. News release. Atossa Therapeutics, Inc. November 20, 2023. Accessed November 4, 2024. https://tinyurl.com/33xamfc8