Breast cancer is the leading cause of cancer death in American women, with around 280,000 women diagnosed annually, so anything that can predict the path of the disease and hopefully prevent its occurrence or its reoccurrence in patients would be very welcome indeed.
One company looking to tackle the issue is Seattle-based Atossa Therapeutics Inc (NASDAQ:ATOS), a Nasdaq-listed clinical-stage biopharmaceutical company seeking to develop innovative medicines in areas of significant unmet medical need in oncology, with a focus on breast cancer.
Atossa - which is named after Princess Atossa, the wife of King Darius, ruler of the Persian Empire, and the first woman in recorded history with breast cancer – is developing a proprietary oral formulation of endoxifen, the most active metabolite of the US Food & Drug Administration (FDA) approved Selective Estrogen Receptor Modulator (SERM) tamoxifen, that does not require liver metabolism to achieve therapeutic concentrations and is encapsulated with a patented formulation to bypass acidic conditions in the stomach.
Studies have demonstrated that the anti-estrogenic effects of tamoxifen are driven in a concentration-dependent manner by endoxifen. In addition to its potent anti-estrogen effects, endoxifen has also been shown to target PKCβ1, a known oncogenic protein. It is truly a double-edged sword against breast cancer.
Atossa’s endoxifen has been shown to be well tolerated in Phase 1 studies and in a small Phase 2 study of women with breast cancer. The company is currently studying endoxifen in three Phase II trials; one in healthy women with high, measurable breast density and two focused on women with ER+/HER2- breast cancer. Atossa’s endoxifen is protected by two issued US patents and numerous pending patent applications.
Proactive sat down with Dr Steven Quay, Atossa’s president and chief executive officer to find out more.
Proactive: How did Atossa come to focus on developing a propriety oral formulation of endoxifen for use as a breast cancer therapy?
Dr Steven Quay: About 15 years ago, I asked a pretty simple question: Why isn’t there a Pap smear for breast cancer? Now what I meant by that was, take us back to 1954 when about 115,000 women were getting cervical cancer every year: Dr George Papanicolaou at NYU – the “Pap” of the test - came up with an observation that if you scrape the cervix and put the smear under a microscope you can see sort of three levels of transition - from normal cells, to many normal cells, called hyperplasia, to many normal cells that look funny, the technical term, atypical hyperplasia, and then cells that are just no orientation to each other at all, which is carcinoma in situ (CIS). This is the last stage of local cancer that is typically 100% curable. Untreated, CIS spreads throughout the body and becomes a condition that kills patients. So, Dr Papanicolaou basically said, I have a test to tell you the 10-year path of getting cervical cancer, even if you don't have cancer.
A lot of people think the Pap smear is thought to be a cancer test but it is really not, it's a predictor of future cancer years down the road. Fast forward to now, the impact of the Pap smear is that we've gone from 115,000 cases a year to 11,500, primarily because that test gave us a window into the decade-long march of cervical cancer, allowing treatment while it is still in the cervix. Of course, now we have a vaccine.
All of this factored into my thinking about whether there could be something similar for breast cancer, and that has been the mantra of Atossa Therapeutics ever since. The company, named for the first woman with breast cancer and dedicated to the generations of her ‘sisters’, has focused on this simple task: to try to give doctors a decade look into the progression to breast cancer. I think we've made a lot of progress.
So, what have you done in breast cancer that parallels the Pap Smear and what is the differentiator for the company’s endoxifen formulation?
Okay, so, before I get there, let’s look at the similarities between the Pap Smear and where we are with breast cancer.
The Pap smear scrapes the cervix, and you put it on the microscope and look for those changes. It turns out that a mammogram for breast cancer detection looks at not only little, tiny crystals of basically salt, which are dead cancer cells, but also at a general darkness of the mammogram itself, which can be quite dark, or it can be almost completely white. And it turns out that this background density is an indicator of future breast cancer, just like those cell changes in the cervix were predictors of future cervical cancer.
With the mammogram, as with the Pap smear test, we're now trying to intervene and seeing if we can change the background, back to a more normal density with a drug I invented called endoxifen which inhibits things that are stimulated by estrogen. The cells in the breasts that cause cancer are stimulated by estrogen, as are the ovaries and the uterus in women. Endoxifen goes to where estrogen would go, it sits in the receptor, and it basically blocks it not letting estrogen engage. If the receptor is a lock, endoxifen is a better key than estrogen itself, and in going into the lock it turns off the estrogen function.
So, with respect to our formulation, I invented a patented delivery mechanism for endoxifen. In drug delivery, the only time you don't need a formulation is if you give something intravenously, meaning something goes right into the bloodstream. But for every other drug delivery method, there usually must be some special secret that takes this molecule from the laboratory and keeps it stable so you can put it in your mouth, swallow it, get through the acid of the stomach and the harsh environment of the small intestine and can get taken into the bloodstream to get to the body.
And so, our formulation is quite unique. It allows the drug to get through the stomach - any other formulations of endoxifen get destroyed in the stomach; so that was the hurdle I had to invent our way over. So, we've got patents for endoxifen itself, we've got patents for the formulation of it, and in this business, of course, it's only patents that allow a little company like Atossa to take on the giants like Pfizer and AstraZeneca.
The company is involved in three phase II trials. How do these compare and what are the timescales for results?
If you think of breast cancer as a disease that is a continuum, we've talked about the prevention phase but then there clearly are women who have breast cancer and, for these women, the two treatment stages available beyond surgery are called neoadjuvant and adjuvant. There is a window of time between the diagnosis and the definitive treatment, which is still surgery plus radiation, which is called the neoadjuvant setting. With breast cancer, this window can be as short as about three weeks, and as long as about six months. With surgical intervention, usually, now we don't take the breast off, we do what's called a lumpectomy, a partial mastectomy. So, the purpose of endoxifen during the five years after definitive surgery would be to prevent recurrence in that same breast. But once a woman has breast cancer, she also has a higher risk of cancer in the other breast, so the five-year adjuvant treatment is aimed at both local recurrence and the prevention of a second tumor.
With respect to the first endoxifen trial - the EVANGELINE trial, which was just profiled at the big American Society of Clinical Oncology (ASCO) meeting in Chicago - we are taking women in the neoadjuvant phase, where they have just been diagnosed, but the subtlety here is they all must be pre-menopausal, meaning their ovaries are capable of making estrogen. One of the challenges in breast cancer treatment in this population is that if you give an ordinary inhibitor of estrogen activity to a woman who can make estrogen, her ovaries basically say something's wrong here and pump more estrogen into the bloodstream, which can defeat the purpose of a weaker drug. But because endoxifen is so much stronger than all the other blockers of estrogen we believe it will be able to block the function even in the presence of potentially higher estrogen in pre-menopausal women.
The EVANGELINE Phase II trial will be made up of 175 women at up to 25 sites and we are measuring a couple of endpoints. One of them, Ki-67 is basically a percentage, a fraction of the number of cells that are dividing at any point under the microscope as the numerator and the number of total cells in the denomitor. So, a Ki-67 of 25 would mean one of four cells is dividing, and then you want to see that reduced by the action of the drug. Reducing it means you are slowing or stopping the growth of the tumor.
The second Phase II trial is called the I-SPY trial and is for the same neoadjuvant population but includes both pre and post-menopausal women. The I-SPY trial is an incredible process that Laura Esserman, a doctor at UC San Francisco, has put together and is called an adaptive clinical trial, which allows you to begin a trial, get some data during the process, and adapt the treatment in the middle of the trial. This is only allowed by some very advanced statistics, but it's a very powerful way to get quick information which we are really excited about. Dr Esserman was one of my students when I taught at Stanford Medical School.
The third trial is for the earlier phase of breast cancer, the prevention phase, and is called the Karisma-Endoxifen trial which is being undertaken by the Karolinska Institute in Sweden. What we are doing in this trial is trying to actually test the thesis that mammography is the same as the Pap smear, in that we are going to take women with high breast density by mammography and try to reduce it over a six-month period of time, when the women will take a pill of endoxifen or a placebo pill daily. Our vision for the future is that a woman will not need to worry about her breast health, unless she has a serious family history, until about age 40 and then have a mammogram where a doctor can say the good news is there is no cancer but the bad news is you have pretty high density, so here's a prescription for six months of this drug called endoxifen which we know from clinical trials lowers the density and we know that that will greatly reduce the risk of future breast cancer. That is the vision of the future that drives our work 24/7.
The Karisma-Endoxifen trial is enrolling 240 women with six months on the drug, and then if there is a reduction in density, we're looking at the durability of the reduction when women stop taking the drug – so, can we reduce the density over six months and does the density stay down 18 months later? I think we're going to be fortunate in the context that I think six months will sort of set the clock back over a decade for cancer risk and patients will not need lifetime treatment for this. The idea of being able to intervene and prevent maybe 200,000 estrogen receptor positive breast cancers a year in the US, maybe about two million women worldwide, is a pretty exciting thing to be doing in the eighth drug that I've invented and developed.
At the end of the first quarter of 2023, Atossa had $104 million cash or cash equivalents on its balance sheet. How much runway does this offer?
Just to be clear, we have patents around both the composition of endoxifen, the chemical itself and the formulation, which I think is an important point for our shareholders, that every dollar we invest in our clinical trials is going to be protected by the patents that are the foundation of all that we do. So, having about $104 million in the bank gives us several years of runway. We don't really talk about our burn rate, but you can look at it historically and I think the math would suggest we have over three years of runway at our current burn rate. Obviously, the more trials we do, and the more work we do, we'll spend money a little bit quicker. But the key is that over the next quarter, six months, one year, and multiple years, without raising more cash, without diluting the shareholders, we're going to create great data, which translates into value propositions for our shareholders.
In my experience, there's two things that we know big pharma look for when they want to partner with a little company. Number one is Phase II data that's compelling. And second, they want to see evidence of some sort of agreement with the US Food & Drug Administration (FDA) on the details of the Phase III trials, the final trials before approval. Big pharma likes to do Phase III trials themselves, but they love the idea of having a handshake with the FDA around what that program will look like and what the indication will look like; something they can hand to their marketing people to see how much this drug is worth given the profile that the FDA has tentatively agreed to. So, those two pieces are the things we're going to be developing over the next six to 12 to 18 months.
I think it’s quite clear what you bring to the company as its president and chief executive officer, so what should Atossa investors expect in the near to medium term?
We will continue enrollment in our three Phase II trials and will provide updates on the three clinical trials. There's a nuance in the EVANGELINE trial where we are first going to do blood levels called the PK run-in and that will be a readout that will be near term. So, that will be an important checkbox as it will give people visibility around that trial. Meanwhile, the I-SPY trial enrollment is going quickly, so there should be visibility around the additional patients there.
We are also always looking for additional opportunities to create a product portfolio around our patented endoxifen. If you think about a drug that's designed to inhibit estrogen, the process is to start looking in the body asking if there are any other cancers that estrogen might be related to other than breast cancer. In fact, there are some. So, I think what you'll see over the coming years is Atossa looking at this valuable drug that we have developed that stops estrogen activity no matter what it is doing in the body, and asking what other tumors estrogen might have an effect in. We are going to want to sort of play in that sandbox with our drug to try to broaden the value proposition for endoxifen.
The most successful cancer story to date is the near eradication of cervical cancer, starting with the pioneering work of Dr George Papanicolaou. I would like to see Atossa Therapeutics writing the next chapter for breast cancer, with endoxifen leading the way.
Contact the author at jon.hopkins@proactiveinvestors.com