My name is Emily Bodnar, and I'm an equity research analyst at H.C. Wainwright. I'm pleased to introduce Dr. Steven Quay, who is the Chief Executive Officer and President of Atossa Therapeutics. Maybe to start, can you provide us with some background on your lead asset, (Z)-endoxifen? What exactly is (Z)-endoxifen, how does it differ from the prodrug tamoxifen, and do you believe that there's potential for it to be superior in efficacy and safety versus tamoxifen?
Yeah. Great, well, it's great, it's great to see you again, Emily, and it's great to be at the H.C. Wainwright Conference here. So tamoxifen, when it enters the body, produces twenty-one different chemicals. A couple of them are good, most of them are neutral, and actually, a couple of them are bad. One of the best ones is endoxifen itself, so it really isn't a fair comparison when you think about tamoxifen versus endoxifen. Endoxifen has all of the efficacy activity of tamoxifen, with none of the attributes of the other twenty things you don't really need to take.
How does (Z)-endoxifen function as a SERM and a SERD? W hat do these classifications mean in the context of the current treatment landscape for HR-positive, HER2-negative breast cancer?
Yeah. So both of these activities are things that it does on the estrogen receptor. A SERM blocks estrogen by interfering with the binding of estrogen, and that's a simple process. A SERD actually changes the shape of the estrogen receptor, causes it to be degraded, which is a more powerful activity, and so that's kind of the differentiation there.
Okay, and, as you mentioned, some of the tamoxifen effects are harmful, and I think one of the main ones is the high rate of vasomotor adverse events, which are associated with it. Do you believe that (Z)-endoxifen could potentially have lower rates of those adverse events, and what has the experience been like in the clinical trials to date?
Yeah, Emily, that's a pretty easy one because, unfortunately, these vasomotor side effects, night sweats, hot flashes, happen about 80% of women. So we are seeing much less than 10%. We're not sure that it's even different from placebo, in these women, so it's dramatically different, and that's... We're really gratified to see that.
Okay, maybe to start with the breast density program that you have going on, given you've kind of guided to top-line data pretty soon. What has been the evidence with tamoxifen in reducing measurable breast density, and how did that kind of influence your ongoing program there?
Yeah, this is a very important historical point. So back in 2011, a scientist at the Imperial College London named Jack Cuzick showed that if he gave tamoxifen to women and they had a reduction in their density after one year of treatment, when he looked out five years, he had a 63% reduction in cancers. This was a phenomenal finding and would've predicted that you would've been able to prevent breast cancer. Now, the problem is, this back to the 80% of tolerance issues with respect to tamoxifen. So we have the drug endoxifen that can, we believe will have that effect, and with a side effect profile, I think we're in a very good shape to actually enter the space of preventing breast cancer.
What was the driving factor with choosing a low dose of (Z)-endoxifen, based on, you know, low doses that were evaluated of tamoxifen? D o you expect that efficacy would be maintained with a low dose compared to the higher doses you're using in your cancer programs?
Yeah, I mean, that's a kind of in-the-weeds question. But, so tamoxifen is given at 20 milligrams each day to women. We're testing for density reduction at 2-4 milligrams of endoxifen, so why would that necessarily work? But what we did was the important thing is, what are the blood levels of endoxifen? W hen you look at them in, you know, after 20 milligrams of tamoxifen and then what you get with 2 and 4 milligrams of endoxifen, we're actually getting higher blood levels of the most active ingredient. So we're pretty confident we're in the right level of oral drug versus the blood levels that you get.
Maybe give us some expectations for the top-line results that you're expecting to have in the second half of the year. Is there a certain reduction in breast density that would be considered clinically meaningful based on experiences we've seen with tamoxifen?
Yeah, so as I kind of mentioned before, so there's three dosage groups. There's a placebo, a sugar pill, there's a two-milligram and a four-milligram dose. So we're expecting to see a significant difference between the two and the four as a group and the placebo, and then it'll be very interesting to see if we see a dose effect between the two and the four.
What are the current options for women who do have high breast density currently, and how do the different roles of ultrasound act in terms of detection, and why do you believe there's kind of an unmet need in this space?
Yeah, so this is a really important point, 'cause up until now, we've been talking about a woman with high density and the downstream incidence of cancer in that woman. But there's a second negative effect of the density itself, and that is that it makes it hard to find lesions in a mammogram per se. So the you know, cancers or DCIS are small, white lesions. The background density is white, so as some people have said, it's a little like finding a polar bear in a snowstorm. So being able to reduce the density will not only affect downstream incidence of cancer but make current detection easier. Right now, a woman with high density has to either go to, you know, an ultrasound or perhaps an MRI. Sometimes insurance doesn't cover that.
They can be very expensive and inconvenient, so we see this as a nice second benefit of the endoxifen effect.
The FDA has recently announced a new requirement for physicians to have to inform patients if they do have high breast density, and I believe that's going into effect in September, so how do you expect that to kind of change the landscape for a potential need for a therapy?
Yeah, so right now, a woman gets a mammogram every year or every two years, depending on, you know, her, the group that she's in. T he report now simply says, "You have a lesion, you have to come back," or, "You're perfectly fine." The additional information will be, you know, you have high density or intermediate density or low density, and that can trigger additional imaging, probably also triggers some worry.
Being able to have a drug that can address that, where the physician says, "Hey, look it, you have high density, you know, there's some issues around that with increased cancer, but this clinical trial done by Atossa showed that if you take this drug for a few months, six months perhaps, you can lower your density and then lower your incidence of cancer." That would be hugely beneficial for, there's 39 million mammograms a year. Ten million women are gonna get a report they have high density, so it's a lot of women.
So going along with that line, how do you kind of think about the total potential market opportunity in this segment? A re there certain types of women or certain types of levels of density that might be more beneficial for a treatment like endoxifen?
Yeah. So the density it used to be divided up into A, B, C, D, based on just the visual appearance from the radiologist. There are now FDA-cleared measurements that give you a scale from one to a hundred. So like everything, there's a group of women who have the highest. The 20% of the women who have the very highest density, they have about 55-60% of all of the cancers, so that will really be our initial target in going after that top 20% of women.
All right. How do you kind of think about next steps for this program beyond the current phase 2 study that's ongoing?
Yeah. So what we want to do is we want to have this drug looked at for what are called interval cancers. So this is a cancer that occurs between the two mammograms. We believe that if we can identify the top 20% of women with high density, give them endoxifen for a period of six to maybe a year time, and then repeat a mammogram, we can reduce the number of incidents of interval cancers between there. In some measurements of the highest density, there are 26 women per thousand that have an interval cancer. So you can see it's gonna be a large trial, but still, you can get to some pretty good numbers if you expect a 60% reduction in cancer.
Okay, great. Maybe moving to the neo adjuvant cancer program you have ongoing. That program is focused on the HR-positive, HER2-negative breast cancer, and specifically patients who are premenopausal. So maybe discuss the reasoning for choosing this particular patient population.
Yeah. T he EVANGELINE trial, as you say, is in premenopausal women with ER-positive breast cancer. It's a large population, about 640,000 women in the world. The challenge is, because they have functional ovaries, when you suppress their estrogen effect with a hormone therapy, the ovaries tend to overproduce the estrogen, and a lot of times, if the hormone therapy is not strong enough, it can actually overcome the anti-tumor effects. Because endoxifen is such a strong inhibitor of estrogen activity, we believe that it actually will be able to overcome the effect of ovaries. Now, what is done currently is something called ovarian function suppression, where basically through an injectable drug and an oral drug, the ovaries are completely shut down. This has really strong quality-of-life issues for women that make it very difficult to tolerate.
So we're hoping that we can suppress the tumors without having to suppress the ovaries at the same time, and that would be a game changer, according to people like Laura Esserman at UCSF.
Sorry. You recently had run-in data that you presented at AACR in April this year from a 40-mg dose in that study. T hen you announced that you're increasing the dose to 80 mg. So maybe just discuss the results that you saw at the 40 mg and why it made sense to increase to the higher dose.
Yeah. So I, as I think I said earlier, is that this drug is bifunctional in that it hits the estrogen receptor at some doses, and then another pathway, called protein kinase C beta, at a slightly higher dose. So we knew that the 40 milligram was gonna saturate the estrogen receptor. We were gonna get all of the benefit there at 40 milligrams, and it was important to see what happened downstream, four to six months later, at the time of surgery, at that dose. Extremely gratifying. We saw, you know, a complete MRI response with complete ablation of the tumor, partial responses in all of the women. So this is kind of unprecedented in that space.
But we'd still like to get to the higher doses, because there are some women who have more aggressive tumors, measured by Ki-67, where they really do need something in addition, for example, the protein kinase C activity. So that's what we'll be looking for in the 80-milligram dose.
W hat is kind of the importance of inhibiting PKC beta-1? Y ou noted that you would need a concentration of 500 to 1,000 nanograms per milliliter to achieve that. I s that what you're achieving with the 80-mg dose now?
Yeah, we're getting into that range, and that's a range that's established in a test tube in the laboratory. Y ou know, patients will tell us what the right dose is by the response of their tumors here. But again, about 30% of women who have ER-positive breast cancer, you know, 70% you can treat with monotherapy for endoxifen for ER-positive. But about 30% need something in addition, because their tumors are even more aggressive, and we think that the PKC beta activity for endoxifen may be exactly what they need to achieve monotherapy suppression of those high-risk cancers.
... All right. Have you completed the 80 mg run-in cohort at this point, and should we be expecting any additional data from the EVANGELINE study in the near term?
Yeah, you know, we're recruiting patients. We have new centers. I mean, Yale Hospital just joined us. So we're going to be reporting data at sort of all of the conferences coming up this fall. Y ou know, I think to be seen later in terms of the data, but we're very pleased with what we're seeing now.
Okay, great. You're also evaluating a similar indication in the I-SPY 2 study. Are you still on track to present data from that cohort in the second half of the year? H ow does this cohort differ from what you're looking at in the EVANGELINE study?
Yeah. Yeah, so the I-SPY network, which was built by Laura Esserman at UCSF, is probably the largest adaptive clinical trial ever developed for any disease whatsoever. W hat we're doing in that trial is having premenopausal women, just like in EVANGELINE, but also including postmenopausal women. Now, in that case, about 40% of the women have a severe reaction to the aromatase inhibitors that these women can take. It's typically in arthritis, and it can sometimes be debilitating. So just like we want to avoid ovarian function suppression in premenopausal women, the opportunity to avoid aromatase inhibitor arthritis in the postmenopausal women is a really important opportunity. We're pleased with the recruitment in that trial at this point.
Do you believe the results from that study would be a good benchmark for the EVANGELINE study? H ow should we think about the different doses that you're evaluating and sample sizes?
So this is important because we have the 2-4 milligram in the prevention trial, we have a 10 milligram in I-SPY, and we have 40 and 80 milligram in EVANGELINE. So it's very important at this stage in our development to understand the biological effects of each of these different doses because we're looking at very different conditions. Y ou know, preventing breast cancer, you have almost no tolerance for side effects because, you know, you're trying to prevent something that actually hasn't happened. Treating a woman with an aggressive cancer at a very high dose to perhaps have some side effects is a very different picture.
Being able to span this range at this point in our clinical development will be really valuable for both us, our partners, our shareholders, in really setting the metes and bounds of what endoxifen can do.
You're also looking at a cohort in combination with the CDK 4/6 inhibitor abemaciclib. So maybe comment on why the combination might be beneficial in the neoadjuvant setting, and what kind of drove the decision to look at this combination?
Yeah, that's an incredible question. So we believe we're probably at the forefront of all companies in breast cancer research using artificial intelligence to find activities or synergies that would just be impossible for the human brain to find. What we did was we looked at the entire transcriptome for over 2,100 different drugs. Now, the transcriptome is 23,000 signals of proteins being made on a minute-to-minute basis in a cell. So you multiply that process by endoxifen and by 21 other drugs, and you come up with, you know, what drugs work and what drugs don't work. A bemaciclib, which is a CDK 4/6 inhibitor, was one of the very best drugs. So it was very gratifying to be able to go to I-SPY, to be able to go to Lilly and say, "Hey, look at..."
With this data, we got, you know, one plus one is more than two." So we're very pleased to have dosed our first patient in that trial. Again, it's the kind of trial where they'll be on drug for four to six months. They'll have their surgery. We will repeat the detailed molecular analysis to verify that artificial intelligence approach. But this is really a remarkable, where we went from an in silico, you know, generative AI prediction a hundred and eighty days ago to a woman being dosed in the I-SPY trial, and that's just unheard of, that I'm aware of.
You recently announced that you increased the dose in that cohort to 80 mg, which is the same dose that you're looking at in EVANGELINE now. Is that—was that driven by the results that you've seen in EVANGELINE so far?
No, it's driven by the severity of the disease in the patients. We want to give them the best opportunity to have the full activity of endoxifen. We continue to see a very nice safety profile as we go up in dose, so that also gives the physicians, you know, the confidence that they can really push the dose, you know, push the PKC beta activity, for the benefit of the patients.
Great, and maybe as a last question, can you walk us through your upcoming milestones and catalysts for the remainder of the year and as we kind of look into 2025?
Sure, sure. I mean, I think we've hit all of them, but, you know, if we summarize them, kind of in some order here, the density results will be the next thing we'll be reporting on density reduction in this six-month trial from the Karolinska Institute in Sweden. After that will be 10-milligram data out of the I-SPY, and then finally, the 80-milligram run-in cohort, where we'll be able to give you PK data, blood level data, and early efficacy data with Ki-67 and some of the imaging studies, like we did with the prior dosing of the EVANGELINE trial at 40 milligrams.
So that's between now and the first quarter of next year, and there'll be some exciting highlights for 2025 as we begin to work through our budget and our goals, with our board on what 2025 will look at. It's very exciting.
Great. It sounds like you have a big second half of the year ahead, so definitely looking forward to seeing those results. Thank you so much, Dr. Quay, and thanks everyone for listening in. I hope everyone has a great rest of their day.
Thanks, Emily. Take care.