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Atossa Therapeutics Anticipates 'Data-Driven' Year in ER-Positive Breast Cancer

March 08, 2024 | Catherine Shaffer

NEW YORK – Atossa Therapeutics is anticipating a series of Phase II clinical trial readouts in 2024 and beyond that it hopes will secure a path to market for its selective estrogen receptor modulator (Z)-endoxifen.


(Z)-endoxifen is a downstream metabolite of tamoxifen, an older breast cancer drug that is still commonly used by patients who can't tolerate aromatase inhibitors. Tamoxifen is converted to endoxifen by the cytochrome P450 2D6 enzyme, and a majority of the anti-tumor activity of tamoxifen is attributable to endoxifen.

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 Atossa is developing the Z isomer of endoxifen as a more potent and readily bioavailable alternative to tamoxifen that it says could have applications spanning preventive, neoadjuvant, and adjuvant breast cancer treatments.

Atossa CEO Steven Quay calls the drug a "triple hitter" because, in addition to blocking the estrogen receptor, the drug also induces degradation of the receptor and inhibits protein kinase C beta (PKCβ), an enzyme involved in programmed cell death. That's important, Quay said, because other selective estrogen receptor modulators and degraders don't induce cell death.

For example, Quay explained, a woman may have recurrence 15 years or 20 years after successful breast cancer treatment in part because the endocrine therapy she had at the beginning never actually killed the cells, and when the patient stopped taking that medicine five years or even 10 years after treatment, it had a chance to grow back. "Endoxifen uniquely kills the cells," Quay said. "Our hope is that it sterilizes the body."

Quay founded Atossa, which is named after the Persian Princess Atossa, who had the earliest documented case of breast cancer around 450 B.C., to discover interventions for the detection and treatment of breast cancer in its earliest stages, focusing on the precancerous hyperplasia stage.

In breast cancer, mammographic breast density is a surrogate marker for hyperplasia, representing up to an eightfold increase in the risk of future cancer. "We're using that basically like the atypia that is seen with cervical Pap smears," Quay said, noting that, at that early point, the tissue changes seen are still reversible. "Our goal is to prevent the 80 percent of breast cancers that are [estrogen receptor]-positive by finding the [precancerous] changes in the dense breast and then treating those."

The Seattle-based company has patents covering methods of use, indications, compositions of matter, and formulations for (Z)-endoxifen, a well-studied compound that has been previously tested in Phase I and Phase II trials with a favorable safety profile.

Atossa is itself evaluating (Z)-endoxifen in several Phase II clinical trials. In the open-label EVANGELINE trial, researchers are comparing treatment with (Z)-endoxifen alone, (Z)-endoxifen plus TerSera Therapeutics' GnRH agonist Zoladex (goserelin implant), and Pfizer's aromatase inhibitor Aromasin (exemestane) plus Zoladex in premenopausal women with ER-positive, HER2-negative breast cancer in the neoadjuvant setting. Initially, they will establish an optimal dose of (Z)-endoxifen in 18 study participants. After that, the remaining patients will be randomized to one of the two (Z)-endoxifen experimental arms or the active comparator arm. Researchers will monitor treatment response via the cellular proliferation marker Ki-67. Patients who are showing response to treatment based on Ki-67 after four weeks will continue treatment for 24 weeks or until surgery.

EVANGELINE is an important trial, Quay said, because it can potentially demonstrate robust anti-cancer activity of (Z)-endoxifen in premenopausal women without ovarian function suppression. Standard anti-estrogen therapy for premenopausal women with estrogen receptor-sensitive breast cancer requires concurrent therapy to suppress all ovarian function, effectively inducing premature menopause. In contrast to other anti-estrogen drugs, Atossa's preclinical studies suggest that (Z)-endoxifen blocks the estrogen receptor powerfully enough that suppression of estrogen production by the ovaries is not necessary.

"It's a major change in quality of life," Quay said. "About half of women stop treatment within one year because the side effects are so draconian."

Quay also noted that if EVANGELINE is successful, it would represent a significant advance for neoadjuvant therapy.

"Eighty percent of [ER-positive] breast cancers are not candidates for neoadjuvant [therapy] in the normal sense because nothing has worked that quickly to make the changes necessary to show a clinical benefit," Quay said. However, in a pilot trial conducted in Australia, Atossa found that just 14 days of neoadjuvant therapy with (Z)-endoxifen reduced the growth of cancer cells.

Atossa plans to share results from EVANGELINE at the American Association for Cancer Research meeting in April.

Atossa is also developing (Z)-endoxifen in additional patient groups beyond premenopausal women with breast cancer. In the Phase II KARISMA trial, Atossa is evaluating two doses of (Z)-endoxifen compared to placebo for reduction of breast density in premenopausal women identified during mammography screening as having BI-RADS score B, C, or D breast density. Quay said that ultimately, that could allow doctors to prescribe a six-month course of (Z)-endoxifen to reduce the breast density and improve the effectiveness of subsequent mammography screening for identification of cancers. The trial, though, is not structured to measure the risk of breast cancer occurrence post-treatment. Atossa enrolled the last patient in that trial in December and expects to report data in the second half of 2024.

Researchers are also studying (Z)-endoxifen within the I-SPY 2 umbrella trial sponsored by Quantum Leap Healthcare Collaborative as a neoadjuvant therapy for ER-positive breast cancer in pre- and postmenopausal women. In that trial, investigators are treating participants for six months with (Z)-endoxifen and evaluating pathologic response via blood biomarkers and MRI imaging after six months of therapy. Investigators completed enrollment in February.

Each of the seven US Food and Drug Administration-approved drugs Quay previously developed has been marketed by a company that is not his own, and that's the likely path for (Z)-endoxifen, as well. "We will develop it as if we're going to market it ourselves," he said, but added that all the while they will be assembling the elements needed to appeal to a drugmaker for licensing or acquisition. Those elements include patents, convincing Phase II data, and a Phase III trial design that the FDA has reviewed and indicated could lead to drug approval. "We're going to have Phase II data this year. The next step is to come up with a Phase III design, go to the FDA, and get approvals on those. And obviously, we'll be talking to partners along the way," Quay said.

Atossa also has plans to investigate combination therapies within breast cancer and indications for (Z)-endoxifen beyond breast cancer. Toward that end, the company is eyeing potential tumor agnostic basket trials for the drug to discover other indications.

Quay said the company currently has a three-year cash runway and is anticipating a "data-driven" year which will support advancement of (Z)-endoxifen as a monotherapy and inform decisions around development of combination therapies and other cancer indications.

Reprinted with permission Precision Oncology News, a business unit of Crain Communications © 2024.

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