Encouraging results for endoxifen

Phase 2 study achieves primary endpoint, with topical endoxifen rapidly reducing breast density

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SEATTLE—Atossa Genetics Inc. recently announced that a preliminary analysis from its Phase 2 study of 20 mg daily topical Z Endoxifen showed significant and rapid reduction in mammographic breast density (MBD). Other studies using tamoxifen have demonstrated that tamoxifen-induced density reduction is associated with significant reduction in breast cancer incidence.
Endoxifen is the most active metabolite of tamoxifen. Tamoxifen has been used since 1977 for breast cancer survivors to prevent recurrence, as well as development of new cancer. Tamoxifen is a prodrug and must be metabolized by the liver into active metabolites in order to take effect. Many patients don’t properly metabolize tamoxifen, which means they receive little to no benefit from taking it.
“By delivering the metabolite endoxifen directly to the body, the need for liver metabolism is bypassed. Moreover, results from our Phase 1 study show that our orally administered endoxifen gets to a ‘steady-state’ in as little as seven days, whereas studies by others have shown that steady-state levels of endoxifen from oral tamoxifen can take up to 120 days,” as noted on Atossa’s website.
The preliminary results of Atossa’s Phase 2 topical endoxifen study show that MBD was reduced by an average of 14.3 percent in the group applying 20 mg daily topical endoxifen. In the lower dose group (10 mg), MBD was reduced by an average of 9 percent. These results are based on MBD measurements at the time of study enrollment and again at the time dosing ended, which was a mean of 55 and 88 days for the 20 mg and 10 mg groups, respectively.
Roughly 70 percent of participants receiving 20 mg topical endoxifen experienced a reduction in MBD. Of those, the mean reduction in MBD was 27 percent. There were no significant differences in systemic endocrine or vascular side effects (e.g. hot flashes) in placebo vs. active groups. Systemic side effects were measured using a modified validated symptom questionnaire. The most common endoxifen side effects were skin rashes and local irritation.
Approximately 72 participants eventually developed skin rashes and local irritation and didn’t complete a full six months of dosing, but the study yielded sufficient data to meet the primary objective of determining sample size calculation for subsequent studies. Based on the study results, a subsequent MBD study using topical endoxifen would require approximately 50 participants for the high dose formulation and approximately 100 participants for the low dose group to achieve a successful efficacy end point.
“We are thrilled that our proprietary topical endoxifen significantly reduced breast density. We believe that no other drug, other than tamoxifen, has been clinically demonstrated to significantly reduce breast density. We observed both a strong and a rapid treatment effect, as demonstrated by our topical endoxifen producing treatment results in only 55 days of dosing for the 20 mg dose,” said Dr. Steven C. Quay, president and CEO of Atossa. “This compares to the one year of dosing previously used in oral tamoxifen studies.”
“Because the 20mg dose produced a treatment effect in only 55 days and because daily dosing eventually produced skin rashes and local irritation in most women, the topical form appears to be particularly well suited for short-term use—perhaps less than 60 days with dosing every other day. These data will now inform our decisions about dosing, as well as development of our oral form of endoxifen,” continued Quay.
A study led by Sir Jack Cuzick, director of the Wolfson Institute of Preventive Medicine in London and head of the Centre for Cancer Prevention, concluded that a 10-percent reduction in MBD after one year of oral tamoxifen conferred a 63-percent reduction in estrogen receptor-positive breast cancer after five years. Based on this and other work, Atossa believes the positive results from this study are clinically meaningful in the context of breast cancer risk reduction.
Atossa now plans to evaluate alternative dosing regimens, such as every other day, as well as shorter overall dosing. The company is also preparing a Phase 2 study of its oral endoxifen to reduce MBD, which it plans to begin shortly.
In July, Atossa announced the development of a new proprietary modified-release oral tablet form of endoxifen. This is the form of the drug that the company intends for future clinical studies and commercialization, and the next generation of oral endoxifen following the successful clinical studies of the capsule form of Atossa’s oral endoxifen. A patent application covering the new tablet has also been filed with the U.S. Patent and Trademark Office.
“We are excited to take this next step in our oral endoxifen product development,” stated Quay in a press release. “Based on the abundance of information from our previous clinical studies, we strongly believe in the potential efficacy of oral dosing and intend for this modified-release tablet to be the commercial form of our oral endoxifen. The goal of the modified-release aspect of the drug is to create more even uptake of the drug, which we believe may reduce side effects and improve efficacy.”
As part of the development of the new oral tablet, Atossa began a Phase 1 study in Australia to ascertain the pharmacokinetics of the drug. The study is randomized, double-blinded and placebo-controlled with both single and multiple-doses in two groups, with a total of 24 healthy female volunteers who will be dosed for 14 days. Atossa’s oral endoxifen capsule will serve as the comparator. The first group of the study has been enrolled and dosed.

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