In this BioPharma Boardroom interview, Steven Quay, Founder and CEO of Atossa Therapeutics, outlines the scientific rationale behind developing (Z)-endoxifen as a direct therapeutic rather than relying on the metabolic activation of Tamoxifen. He explains how bypassing variability in the CYP2D6 metabolic pathway could enable more consistent treatment exposure for patients with hormone receptor–positive breast cancer worldwide. Dr. Quay also discusses the potential role of (Z)-endoxifen in combination endocrine therapy with CDK4/6 inhibitors, the emerging opportunity to upregulate utrophin in Duchenne Muscular Dystrophy, and how biotech leaders can help strengthen innovation, biosecurity, and drug development capacity in a rapidly evolving global healthcare landscape.

What was the scientific and strategic rationale for advancing (Z)-endoxifen directly instead of relying on tamoxifen metabolism?

Tamoxifen has been one of the most widely used endocrine therapies in breast cancer for decades, but it’s important to remember that tamoxifen itself isn’t the most active molecule. Its clinical effect depends on the body converting it into active metabolites, particularly (Z)-endoxifen.

The issue is that this conversion happens in the liver through the CYP2D6 enzyme, and that process varies quite a bit from person to person. Genetic differences, drug interactions, and other factors can all influence how much active metabolite a patient ultimately produces. So two patients taking the same dose of tamoxifen can end up with very different levels of the drug that matters.

Another important consideration is dosing. Only about 10–20% of a tamoxifen dose is ultimately converted into (Z)-endoxifen. In practical terms, that means a 10 mg dose of tamoxifen might yield only about 1–2 mg of the active metabolite. Because tamoxifen dosing itself is limited, that places a ceiling on how much (Z)-endoxifen can actually be delivered to the patient.

Our thinking at Atossa was relatively straightforward: if (Z)-endoxifen is the molecule doing the therapeutic work, why not deliver it directly? By administering it orally, we bypass the metabolic variability and provide patients with consistent levels of the active compound.

Strategically, it’s really about refining a well-established mechanism. We’re not trying to reinvent endocrine therapy, we’re trying to make it more precise and predictable.

How does (Z)-endoxifen address CYP2D6 variability, and what does this mean for global treatment consistency?

CYP2D6 variability is one of the biggest challenges with tamoxifen. The enzyme plays a central role in converting tamoxifen into (Z)-endoxifen, and there’s a tremendous amount of genetic diversity in how active that enzyme is across different individuals and populations.

Some patients metabolize tamoxifen very efficiently, while others produce relatively little of the active compound. That variability can translate into inconsistent treatment exposure.

By giving patients (Z)-endoxifen directly, we remove that dependency on CYP2D6 altogether. The drug doesn’t need to be metabolized into its active form—it already is the active form.

From a global perspective, that’s important because CYP2D6 genetic variants are distributed differently across populations. A therapy that delivers the active molecule directly has the potential to provide much more consistent treatment exposure regardless of a patient’s genetic background.

How do you see combination endocrine therapy—particularly with CDK4/6 inhibitors—improving durability and tolerability?

Combination therapy has already had a major impact on hormone receptor–positive breast cancer. CDK4/6 inhibitors showed that if you target the cell cycle alongside estrogen signaling, you can significantly extend disease control.

Where we see opportunity going forward is in strengthening the endocrine backbone of those combinations. If the endocrine therapy is more pharmacologically consistent and easier to dose, it may help improve both the durability of response and the tolerability of the overall regimen.

That’s part of what we’re exploring with (Z)-endoxifen. Because we can deliver predictable drug levels and have flexibility with dosing, it may function as a reliable endocrine partner alongside agents like CDK4/6 inhibitors. Ultimately, the goal is to delay resistance and extend the period during which patients benefit from therapy.

What is the mechanistic basis for utrophin upregulation in Duchenne muscular dystrophy, and how differentiated is this approach?

Duchenne Muscular Dystrophy is caused by the absence of dystrophin, a protein that helps stabilize muscle fibers. Without it, muscle tissue becomes increasingly fragile and gradually breaks down over time.

Utrophin is a naturally occurring protein that’s structurally very similar to dystrophin. During early muscle development, it performs many of the same functions. The idea behind utrophin upregulation is to increase the expression of that protein so it can help compensate for the lack of dystrophin.

Preclinical work suggests that (Z)-endoxifen can increase utrophin expression through modulation of certain signaling pathways. What’s particularly interesting about this approach is that it’s mutation-agnostic. It doesn’t depend on correcting a specific genetic defect, it’s trying to activate a natural biological backup system that already exists in muscle cells.

It also represents a small-molecule strategy in a space that’s been dominated by gene therapies. Small molecules can offer advantages when it comes to manufacturing, dosing flexibility, and potentially broader global access.

How are you prioritizing development and regulatory strategy at Atossa Therapeutics in today’s funding environment?

The current biotech funding environment has pushed companies to be much more focused on where they invest time and resources. For us, that means concentrating on programs where we have a strong biological rationale, meaningful clinical endpoints, and a regulatory pathway that’s well defined.

We’re continuing to advance (Z)-endoxifen in oncology through targeted clinical studies while also exploring opportunities in rare diseases where the underlying biology supports a clear therapeutic hypothesis.

Regulatory engagement is also a key part of that process. We maintain regular dialogue with the FDA to align on study design and development strategy, and we’re pursuing designations such as orphan drug and Rare Pediatric Disease status where appropriate. Those programs can help accelerate development while also strengthening the overall value of the platform.

What role should biotech leaders play in strengthening national biosecurity and domestic drug development capacity?

Biotechnology has become increasingly important not just for healthcare, but for national resilience. The pandemic made it clear that strong domestic capabilities in biomedical research, clinical development, and pharmaceutical manufacturing are critical.

Biotech leaders can play a role by advocating for policies that support scientific innovation while also strengthening the broader ecosystem that makes drug development possible. That includes sustained investment in basic research, regulatory frameworks that encourage responsible innovation, and infrastructure that supports domestic manufacturing.

Maintaining leadership in biomedical innovation isn’t just good for the industry, it’s essential for public health preparedness and long-term national security.