Good afternoon, everyone. I am Manuel Aivado, President and CEO of Aileron Therapeutics . We're delighted you could join us today to learn more about our potential and passion to revolutionize supportive care by delivering the first precision medicine-based supportive care drug, which would also represent the first selective chemoprotective agent. In the following corporate presentation, I will be making forward-looking statements. By way of quick background, I'm a hematologist and medical oncologist by training. I treated cancer patients in Germany for about a decade, and through that work, witnessed firsthand the often horrendous experience patients must endure while undergoing treatment with chemotherapy. In my industry career, I have had the privilege of participating in bringing five drugs to markets, including one that was also developed as a supportive care drug in the oncology space.
I firmly believe in our mission to develop a novel medicine that prevents chemotherapy-induced side effects to help patients fight cancer more effectively and thereby enabling patients to live better and hopefully longer. I'm thrilled to have joining me today two distinguished guests, Dr. Ralf Paus, Professor of Dermatology at the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery at University of Miami Miller School of Medicine, and Dr. Eric Anderson, a medical oncologist and Assistant Professor of Medicine at Oregon Health & Science University, and also an investigator in our ongoing ALRN-6924 trial in patients with advanced p53- mutated non-small cell lung cancer. Just a quick review of today's agenda. I'll be giving a brief overview on our selective chemoprotective agent, ALRN-6924, and would like to share a few thoughts on our vision and our opportunity to completely transform today's supportive care landscape.
Dr. Paus will then walk us through new ex vivo data that were just presented here at the Society for Investigative Dermatology by himself and his colleagues this morning. Data that give us early evidence of protection against chemotherapy-induced alopecia. After that, Dr. Anderson will share some background on chemo-induced toxicities in general and those toxicities in the context of the current management in non-small cell lung cancer. I will then provide an overview of our ongoing clinical trials and upcoming catalysts. Finally, we will conclude with Q&A. Unfortunately, neither Dr. Paus nor Dr. Anderson's schedule this afternoon permit them to participate in the Q&A, but I'm certainly happy to take questions on any of the topics that will be presented today. Let's jump in. Why do we exist? What gets us up in the morning? It's very simple.
It's our vision to bring chemoprotection to all patients with p53- mutated cancer, regardless of type of cancer or chemotherapy. We're determined to solve a serious problem that affects millions of cancer patients worldwide, and that is the problem of chemotherapy-induced toxicities. Throughout today's presentation, we will be touching on that multifactorial nature of this problem. In essence, if you know who has experienced cancer, you've been firsthand witness to their struggle with chemotherapy-induced toxicities, and those toxicities occur for one single reason. Because in the process of killing cancer cells, chemotherapy also kills normal healthy cells. Chemotherapy is unable to differentiate between cancer cells and normal cells, and these toxicities range from immediately life-threatening to highly unpleasant and quality of life limiting.
Moreover, these toxicities often lead to dose delays and dose reductions, particularly when we are treating patients older than 60 years, which of course, makes up the vast majority of our cancer patients. Oncologists are constantly making trade-offs between giving the most efficacious dose versus giving patients a dose they can actually tolerate. Stands to reason, of course, that if you're receiving less chemo, that often means fewer cancer cells can be destroyed, and therefore, patients' tumor responses will be worse. Our solution to this problem is our selective chemoprotective medicine, ALRN-6924. We're working to advance 6924 to prevent chemotherapy-induced toxicities before they occur, which is very different than today's standard. We enable the protection of multiple types of normal healthy tissue, and we do this by using a precision medicine-based approach that ensures we are protecting only healthy cells from chemotherapy and not cancer cells.
Now, this slide may look familiar to those of you who have seen our current corporate slide deck. We have been and will continue to be focused on hematologic toxicities, which you see here on the left side of the slide. These are the most feared chemo-induced side effects because they are more likely to occur and more likely to lead to serious life-threatening or even fatal complications. These hematologic toxicities are also the ones that can be most objectively measured. But as we've always explained, 6924, because of its mode of action, also has the potential to protect other types of normal cells. Today, we'll start to talk more about the right-hand side of this slide, as well as we discuss non-clinical data supporting the potential of 6924 to protect against chemo-induced hair loss.
Now, as I referenced, there are a broad range of chemo-induced toxicities because chemo damages multiple types of healthy, self-renewing cells, in particular stem cells. In addition, it's important to understand that different types of chemotherapy have very different toxicity profiles. For example, topotecan, which we studied in our recent small cell lung cancer study, topotecan is associated with a high frequency of all three types of severe hematologic toxicities, as you can see depicted here in dark purple. We established the proof of concept for 6924 as a chemoprotective agent against these severe heme toxicities in this now completed phase I-B open-label study of 6924 in SCLC patients treated with topotecan. The trial established the foundation based on which we are now expanding our clinical development to evaluate 6924 with different chemotherapies with distinct chemo-induced toxicity profiles and in different types of p53- mutated cancers.
The first part of that expansion is our ongoing phase I-B randomized double-blind placebo-controlled trial in patients with non-small cell lung cancer receiving carboplatin plus pemetrexed without immune checkpoint inhibitors. I'll talk more about that trial later, but briefly in the context of this slide, we know that carboplatin plus pemetrexed is associated with multi-lineage heme toxicities, albeit at a frequency that is much lower than seen with topotecan, as indicated here with the light purple color. We knew that going into this trial and therefore designed this trial with a composite endpoint that accommodates for the fact that our drug can protect against multiple different problems at the same time. Then finally, in our phase I-B open label breast cancer trial that we just announced this morning, that started, we will be expanding to yet another chemo in another p53- mutated patient population.
These are patients with breast cancer receiving new regimens, doxorubicin plus cyclophosphamide, followed by docetaxel. Now, this regimen, often referred to as AC+D or TAC, is associated with significant grade 4 neutropenia and about 90% rates of hair loss, with about 25% of patients experiencing permanent hair loss from docetaxel. How can we break with the old paradigm and use one medicine to protect against multiple different toxicities at the same time? This slide will describe how, and it explains how we ensure we are protecting healthy normal cells without protecting cancer cells. In a nutshell, with 6924, we actually treat healthy cells, not cancer cells. We do this by using a precision medicine-based approach that leverages our biomarker, p53, the most common mutation in all of cancer.
We administer our drug ALRN-6924 as a one-hour infusion prior to chemo in patients whose cancers are p53 mutant. ALRN-6924 then activates p53 in normal cells and thereby arrests their cell cycle. Patients then receive chemo, and chemo will now kill only cancer cells because those are p53 mutant and our drug does not shield p53 mutant cells, basically turning poison into a tolerated treatment. While some might think employing a biomarker strategy narrows our opportunity to select our targeted patient population, the fact is that our targeted patient population is enormously large. As this slide shows, there are nearly a million newly diagnosed patients with a p53- mutated cancer in the U.S. each year. As depicted here, the p53 mutation is prevalent across most major cancer types.
Considering that existing supportive care drugs charge $4,000-$8,000 per chemo per cycle, and knowing that each cancer patient will on average receive around six cycles of chemo per year, you'll quickly arrive at an incredible market potential for the U.S. alone. Because of the ubiquitous nature of p53 mutations across all cancer types, and because we treat healthy cells, not cancer cells, our ultimate goal is to collaborate with the FDA to make 6924 available to all patients with p53- mutated cancer who undergo myelosuppressive chemo. What might that look like? I described earlier that we specifically designed our non-small cell lung cancer trial to utilize a composite primary endpoint to accommodate for the toxicity profile of carboplatin and pemetrexed. The chemo is not associated with a high rate of severe neutropenia, as I explained earlier.
Choosing a primary endpoint of severe neutropenia in that specific chemo would not allow us to adequately evaluate the chemoprotective effects that 6924 has to offer. Instead, by using a composite endpoint, we're able to capture multiple events per patient and per cycle across various different toxicities. Looking down the road at a potential pivotal trial, there are some important advantages to this approach, including the fact that the design increases the effect size, thus decreasing the required sample size for such a pivotal trial. The notable disadvantage of this approach is that there is no regulatory precedent for a composite primary endpoint in the supportive care space. Granted, there's never been a drug like 6924 that can safely protect against multiple toxicities in a biomarker-defined patient population. We find ourselves here in a unique situation.
Interestingly, there is a very frequent precedent for what is an approvable primary endpoint in the supportive care space, and that is the duration of severe neutropenia in cycle one. The advantage to this approach, of course, is a faster trial because of the faster readouts, because unlike with the composite, where you're looking across four to six cycles, here you're only looking at the first cycle to collect your data for your primary endpoint. Since this is a well-established regulatory precedent, the risk is probably lower than pioneering a new regulatory endpoint in supportive care. These are just some of the considerations we'll weigh as far as a regulatory pathway for 6924 is concerned. That said, only two factors ultimately will determine our regulatory path. Number one, data, and number two, our subsequent discussions with the agency.
With that, I'd like to turn the presentation now over to Dr. Ralf Paus. By way of introduction, Dr. Paus works at the University of Miami, which is one of the. He runs one of the world's leading laboratories focused on the biology and pathology of human hair follicles, with special emphasis on chemotherapy-induced hair loss, for which the Paus Lab developed leading research models. Given Ralf's unique area of expertise, you can imagine how delighted we were to come across the research he and his team had previously published in 2019, where they described that cell cycle arrest is the mechanism to protect against chemotherapy-induced hair loss. We immediately saw the potential synergies between 6924 and the research Ralf and his colleagues have undertaken.
It's been a wonderful, and I believe, as you will hopefully see, a very fruitful collaboration so far between industry and academia to advance a scientific hypothesis that could benefit so many patients. With this, Ralf, please.
Thanks so much, Manuel, for the introduction. I would like to talk to you about a radically new strategy for preventing chemotherapy-induced hair loss. What I bring to you today are our first data on this that Aileron convinced me to generate for them. They had an easy time to convince me, because for the longest time, I've been one of the actually very few people on this globe who seriously care about chemotherapy-induced hair loss and want to understand how it works and what we can do about it. I'm a professor of dermatology at the University of Miami and have long been interested in what is the pathobiology that underlies hair follicle damage under chemotherapy, and what we can do about it. The compound that Aileron had developed was particularly interesting on many levels.
I would like to tell you more about what we found in order to identify the temporary cell cycle arrest by their compound, 6924, which selectively protects human scalp hair follicles and their epithelial stem cells from taxane-induced toxicity. Chemotherapy-induced alopecia mediated by taxanes is actually one of the most devastating experiences that cancer therapy patients undergo and is often experienced as a life-changing event. This not only can be as dramatic here as you see on this image, but it can persist for many years, if not forever. That so-called acute chemotherapy-induced alopecia then becomes a permanent alopecia. With one of the most frequently administered taxanes, paclitaxel, that is in the range of 10%, and with docetaxel, even in a quarter of the patients.
When you then combine this with other chemotherapeutic regimens, it gets even worse. What we had discovered, first in mice, then in human hair follicles, is that the hair follicle re-responds to chemotherapy-induced damage in two ways. It either undergoes, the so-called dystrophic anagen pathway, where its growth phase is interrupted and disturbed, for some time, it can actually get longer, this growth phase, during which a very imperfect, and structurally, impaired hair shaft is being made, which eventually is being shed, or it undergoes the so-called dystrophic catagen pathway, where the hair follicle rapidly regresses, to then regenerate itself most rapidly. Patients that undergo this pathway will have the most dramatic, most acute, alopecia, but then also regrow their hair shafts, faster.
In the dystrophic anagen pathway, depending on the level of damage these hair follicles suffer, you will either get a loss, a lot of hair loss or less hair loss, but you will also regrow your hair shafts, a little bit later. The second thing happens, the stem cells from which the cyclic regeneration of hair follicles occurs gets massively damaged by taxanes, as we had recently published. Now, the reason why, alopecia can become permanent, in taxane-induced alopecia is that these stem cells get irreversibly damaged.
We had actually shown, in a paper in EMBO Molecular Medicine, 2019, and this paper is the reason why, Manuel contacted me, that paclitaxel induces what's called mitotic catastrophe, a process, whereby stem cells, in this case, simultaneously proliferate and divide and switch on, programmed cell death, apoptosis. In addition, we had shown that this taxane causes much more damage to these stem cells than we had previously thought. Not only does it kick them into apoptosis, but, it also damages the DNA. What we then had gone on to show is that if you temporarily arrest these stem cells, from entering into the cell cycle via a cell cycle inhibitor called palbociclib, another chemotherapeutic agent, this can protect the hair follicle, at least in organ culture, the hair follicles from taxane-induced, cytotoxicity.
The big problem for which we had no solution is how can one protect the body's own cells from this damage without also protecting the cancer cells? This is where ALRN-6924 comes in. As you have heard from Manuel, it activates normal p53 and thus does not protect p53 mutant cancer cells. At a low dose, it causes cell cycle arrest, and only at a high dose it causes cell death. The specific questions we ask now, if we give ALRN-6924 before chemotherapy, how will this impact on the decision of the hair follicle between this dystrophic anagen pathway, which is the one you want to promote in order to reduce the acute initial hair loss?
Does it even promote dystrophic catagen, which might eventually then cause faster hair regrowth, but would give you a terrible initial alopecia? Something that had been not studied at all, what does this Aileron compound do to epithelial stem cell damage in the so-called bulge where these stem cells are located in the hair follicle? The model we use is we get scalp skin or isolated hair follicles from hair transplant surgeons, and we culture them in a serum-free medium, where we then can study multiple things. We can study how fast the follicle grows from the growth phase, anagen, to the regression phase, catagen. We can look at what happens at stem cells. We do this by looking at a number of readout parameters where I don't want to tell you too many details.
I don't want to bore you stiff here with details. If those of you who are interested in that, we have described this methodology in detail elsewhere. Actually happens is after we isolate these hair follicles, we then first treat them with Aileron 6924 . We give them the taxane, paclitaxel in this case, and then after a few days, we stop the culture and look what happened. The very first thing we always look at is we look at hair follicle pigmentation. Now you may ask, so why pigmentation? Well, we figured out many years ago that for hair follicles to make a pigmented hair shaft, this happens in the so-called hair follicle pigmentary unit right here.
Melanocytes, pigment cells, have to inject melanin loaded melanosomes at the exact right position into hair shaft keratinocytes right here. That's how you get a pigmented hair shaft. If you damage the follicle with anything, the very first thing you happen to see is that these melanin granules end up elsewhere where they shouldn't end up, and they become clumpy. These melanin clumps are a very sensitive indicator of whether or not you have hair follicle damage. The very first thing we saw is that, yes, paclitaxel induces lots of melanin clumping while Aileron itself didn't do anything different from the vehicle.
If you combined the Aileron compound and paclitaxel, you had a substantial, really significant reduction of melanin clumping, suggesting that the hair follicle damage was already re-induced by paclitaxel, was reduced by around 6924. We then looked at another question, which is very important. If you treat the hair follicle with a cell cycle arrest-inducing agent such as 6924, what you would expect is that that compound could actually accelerate or stop the growth phase, the anagen phase of the hair follicle, and kick the follicle into catagen by itself without any chemotherapy. That would be good because that would give you a so-called telogen effluvium, a diffuse form of hair loss, an increased form of hair shedding.
That did not happen. If we look at the so-called hair cycle staging and compare the percentage of hair follicles in the growth stage between vehicle and the Aileron-treated hair follicles, no difference. That was very encouraging. Paclitaxel reduced the number of growing hair follicles a little bit, but there was no big difference between any of the groups. The number of apoptosis positive cells in the hair bulb, that's the actual hair shaft factory down here, was not different between the paclitaxel-treated hair follicles and those that were protected by Aileron before you treat it with the chemotherapy. That was a bit disappointing.
We had hoped for a reduction of apoptosis, but since Aileron itself is an apoptosis-promoting compound, it was not at all surprising. What really got us excited is this here. Namely, as expected, paclitaxel induced massive mitotic catastrophe in events, the coincidence of proliferation and cell death in the same cells in the rapidly dividing hair matrix keratinocytes measured by Ki-67 and caspase-3. That was substantially reduced by pre-treating the hair follicles with Aileron. Totally encouraging. We looked at what happened in the stem cell compartment in the bulge cells from these hair follicles that were treated with paclitaxel with or without pretreatment of Aileron, of the Aileron compound.
That was encouraging too, because we showed that indeed, as we had hoped for, the Aileron compound basically froze the stem cells in the hair follicle bulge and completely arrested their cell cycle. What was very, very encouraging in the first experiment when we saw this, we were not sure could we repeat this. Now, all these data I'm showing you are based on hair follicles from three different donors. What we saw in addition is that in fact, 6924 prevents paclitaxel-induced stem cell apoptosis in the hair bulge, which is exactly what you want clinically because you get permanent alopecia after taxane therapy because your stem cells in the bulge get destroyed or irreversibly damaged otherwise.
They, the hair follicle, lose the capacity to regenerate themselves from these stem cell populations. If you compare here the hair follicles, the stem cells in hair follicles treated with taxane itself, those pre-treated with the Aileron compound, you see that there's a significant reduction of stem cell apoptosis. Just what we had been hoping for. Furthermore, these stem cells, as we had found in our 2019 paper, also suffer DNA damage, which has long-term nasty effects on stem cell survival, even months later or sometimes even years later. This stem cell damage, if it cannot be repaired, can have lasting consequences. We look for y-H2AX as a very sensitive molecular marker for DNA damage in hair follicle stem cells.
As expected, paclitaxel, as we had reported before, again dramatically upregulated this damage. Lo and behold, 6924 was significantly reducing this damage, DNA damage again. Finally, what we also had discovered just one or two years ago, is that when you treat human hair follicles with chemotherapy, not only does it induce DNA damage in these cells, and it not only kills these cells and kicks them into apoptosis, it also induces a process that's called a pathological epithelial-mesenchymal transition. Now, if you are an epithelial stem cell, the last thing that you want happen to you is to undergo transformation to a fibroblast, a connective tissue cell type, because then you can never regenerate an epithelial tissue such as the hair follicle.
As for the very first time we show here in these experiments that paclitaxel not only induces cell death and DNA damage in human scalp hair follicles, but it also promotes pathological epithelial-mesenchymal transition, which you can measure with a very nice marker called vimentin. Which is normally never positive and expressed in these stem cells because it's only expressed in mesenchymal cells such as fibroblasts. Again, ALRN-6924 dramatically reduces this. We are talking only about cultured effects of a few days ex vivo. In summary, what could we show here? Now we got really quite excited because this is a very, very novel principle of managing chemotherapy-induced hair loss both acute and long-term.
What we had shown in these organ culture experiments, of course, it has to be so to be seen whether that actually works on the living human being. That on the one hand, the dystrophic anagen pathway is being favored, which suggests a minimization of acute alopecia. The number of mitotic catastrophe events and the overall hair follicle toxicity in the hair bulb, the actual hair shaft factory, goes down after this pre-treatment. Most excitingly, as a preventive device against permanent alopecia, apoptosis, pathologic EMT and DNA damage in the epithelial stem cell compartment of the hair follicle in the bulge up here also is significantly reduced. Therefore, we present here the first proof of principle that acute and permanent taxane-induced alopecia at the condition of this assay we were running here.
Which is the clinically most predictive assay we have in all of hair research for what happens on the human scalp in vivo, can be reduced by pretreatment of human hair follicles with Aileron 6924. Since this is the most predictive model we have in preclinical hair research for clinical outcomes, it indeed promises that we can reduce paclitaxel-induced hair follicle toxicity also in vivo. Encouraging too is also that the compound itself does not promote catagen, and therefore should as such not give you more hair loss than you already are getting as a cancer patient. That we can show here that Aileron 6924 inhibits paclitaxel-induced mitotic catastrophe in the hair matrix suggests that it may favor a milder form of dystrophic anagen.
Justifies, therefore, the expectation that temporary cell cycle arrest by this compound may reduce acute alopecia. But most excitingly, because that's what we had been hoping for and looking for to find such a compound, that it also reduces taxane-induced hair follicle stem cell death and damage, at least under ex vivo condition, and therefore promises to reduce both the incidence and the degree of permanent alopecia after taxane therapy. But most of all of this can happen selectively in healthy hair follicle cells and their stem cells without tumor cells profiting from this. With this, let me thank you Aileron for having encouraged us to do this study. Perhaps most importantly, the postdoc in my lab in Miami who generated most of the data, Jennifer Gherardini. You, thank you for your attention.
Thank you, Ralf. We're delighted about our research collaboration with you and your team. We're very encouraged by these ex vivo findings, and we look forward to seeing how these non-clinical results translate in the clinic to protect patients against chemotherapy-induced alopecia. In addition to protecting from neutropenia in our ongoing breast cancer trial. Switching gears now, I'd like to introduce Dr. Eric Anderson again, who will present his perspective on chemo-induced toxicities related to the treatment of lung cancer with carboplatin pemetrexed, the focus of our ongoing non-small cell lung cancer trial. For those who missed today's introductions, Dr. Anderson is a medical oncologist and assistant professor of medicine at OHSU in Portland, Oregon, and he is an investigator in our ongoing NSCLC trial. Eric, over to you.
Thanks, Manuel. I appreciate the opportunity to talk today about non-small cell lung cancer and chemotherapy-related toxicities as they're seen in real-world oncology practice. Today I'm gonna talk to you about non-small cell lung cancer and chemotherapy-induced toxicities, and the impact they have on our patients and need for innovation in this setting. By way of introduction, my name is Eric Anderson. I'm a medical oncologist. I'm the Medical Director of Community Oncology at the OHSU Knight Cancer Institute in Portland, Oregon. Just some background on non-small cell lung cancer. There are about almost 200,000 patients annually are diagnosed with non-small cell lung cancer in the United States.
85% of all lung cancer is non-small cell, with the remainder primarily being a much more aggressive type called small cell lung cancer, which Aileron also has a recent study of their study drug in. Average age at diagnosis is 70 years old, and the vast majority of older patients experience more significant toxicities than younger patients from chemotherapy of all kinds and all cancer types. 60% of non-small cell lung cancer patients do have a p53- mutated cancer, which is critical for the function and efficacy of the ALRN-6924 drug. The treatment landscape has been evolving pretty dramatically in non-small cell lung cancer over the last five years.
Targeted immune checkpoint inhibitors for PD-1, PD-L1, and CTLA-4, as well as targeted therapies against mutations and fusions in the EGFR, ALK, KRAS, ROS1, BRAF, and MET genes, among others, have transformed the treatment paradigm. Chemotherapy remains the backbone of treatment, particularly for patients with locally advanced or metastatic non-small cell lung cancer. Carboplatin and pemetrexed has over the last 5-10 years become the most common first-line combination chemotherapy regimen for non-squamous, non-small cell lung cancer, as its efficacy is quite excellent and its toxicity, although significant, is somewhat less than some of the other chemotherapy regimens that are used in non-small cell lung cancer.
The dosing, quite commonly these days is using a carboplatin dose of an AUC of 5, which is a lower dose, than was originally studied, as we'll see in a minute, and leads to decreased toxicities. As a result, anytime that you reduce the dose of a chemotherapy drug, you potentially inhibit its efficacy. A carboplatin AUC of 6 dosing does have higher toxicity, but is felt to have better efficacy in many settings. The addition of immune checkpoint inhibitors to chemotherapy regimens has led to most oncologists in the United States shifting to a lower dose AUC of 5. In this study, the 6924 drug is dosed with a carboplatin AUC of 6 in order to ensure that the most effective chemotherapy regimen is given.
In this study, the administration is given four to six cycles of each drug. The drugs are dosed together once every three weeks for four to six cycles. The hematologic toxicities from carboplatin and pemetrexed are well known and well understood. This study from 2005 was one of the first studies that brought pemetrexed into the treatment landscape in the first-line treatment of advanced and metastatic non-small cell lung cancer. In this study, just as the 6924 trial, it was first-line locally advanced or metastatic non-small cell, non-squamous lung cancer. Patients had to have a good performance status with an ECOG status of 0 or 1, which means completely normal function or very good function.
They had to have a neutrophil count that was greater than 2, platelets that were greater than 100,000, and hemoglobin greater than 9. Of note, it's important that you understand that these numbers are there not so much because it's dangerous to give the drug specifically if these counts are lower, but that when you give the drug with patients whose counts are lower than this, you risk causing their counts to drop to dangerous levels and put them at risk of bleeding or infection. Pemetrexed in this study, the Scagliotti study, as well as the 6924 study, is dosed at 500 mg per meter squared with carboplatin dosed at AUC of 6, which is, as noted, a higher dose of treatment. In the original study, they used some supportive care drugs.
One is colony-stimulating growth factor, or GCSF, allowed to treat serious neutropenia. That is a standard of care in the community to this day. However, we generally only use it once we've discovered that the chemotherapy is too toxic to the patient and they require support with this. Erythropoietin, or EPO, was originally allowed as supportive care for anemia. However, we have data since this study has come out showing that it dramatically increases the risk of serious venous thrombotic events and has a black box warning and is no longer used in this setting. In this study, it was found that the neutropenia of grade 3 or greater was present in a quarter of the patients.
Thrombocytopenia of grade 3 or greater was found in almost 20% of the patients, and anemia of grade 3 or greater was found in 8% of the patients. Importantly, febrile neutropenia, which results in hospitalization and often significant morbidity and occasionally mortality, is seen in up to 5% of the patients. Newer data from the era of immunotherapy in addition to chemotherapy here in the Gandhi study, which is also known as KEYNOTE-189, very similar. However, they did, you'll note that carboplatin was dosed much lower of an AUC of 5 in most of the patients in this study. Similarly, you see that their neutrophil counts were required to be 1,500 or higher, platelets, again, greater than 1,000, and hemoglobin greater than 9.
In this case, you'll see that the neutropenia, thrombocytopenia were similar to the rates that we saw in the prior study, although neutropenia is a bit lower. Interestingly, anemia is quite a bit higher in this study as well. What's important is that how this works in the real world. We have historical trials, and most of the time in clinical trials, we're focused on objective measures of toxicity that you can see, like neutropenia and anemia. The reality is that in the real world, most patients don't stop treatment because of those problems. They stop treatment primarily for more subjective side effects. Just as I mentioned a little bit before, to give you some context here, I'm the medical director of an academic community-based oncology group.
We have five clinics, about 14 oncologists, and we cover a 250 sq mi catchment area, very large portion of Oregon and Southwest Washington. I personally see three to four new non-small cell lung cancer patients monthly. My partners see similar to slightly more of those patients as well, and I also treat a large number of patients with gastrointestinal and breast cancers. The vast majority of my patients with non-squamous, non-small cell lung cancer receive carboplatin and pemetrexed with or without immunotherapy as their first-line treatment. It's important to note that cisplatin and pemetrexed is often used in patients who have had their stage 2 or 3-A lung cancers removed surgically as what's called adjuvant or post-operative chemotherapy. This is a very common chemotherapy regimen in this setting.
As I mentioned, nearly all chemotherapy regimens have multiple overlapping and additive toxicities, and they can be objective and subjective, and you can see some of these here. I think it's important to note, though, that the subjective toxicities are the ones that are the most common reason for patients to choose to stop treatment. Fatigue, nausea, neuropathy, diffuse body aches known as myalgias and arthralgias. Those are what keep people from coming back to get chemotherapy in many of these settings and for them to choose to stop treatment. As an example, the first patient that we enrolled on the 6924 trial stopped chemotherapy not because he had issues with his blood counts going down or any other objective toxicities, but because he could not tolerate many of the subjective toxicities.
As I noted before, the vast majority of patients with metastatic non-small cell lung cancer are 70 or older, and a vast majority have performance status of ECOG 1-2, which makes the fact that their chemotherapy regimens cause them more toxicity than younger and fitter patients. At the moment, as far as supportive care for chemotherapy-induced toxicities, we don't have a ton out there. The classic example that we use is anti-nausea medication or nausea prophylaxis, which we've been very successful at improving over the last 20-30 years. However, supportive care for bone marrow toxicity, which is what the 6924 study is focused on, is quite primitive, to be honest. For neutropenia, we can use colony-stimulating growth factors such as GCSF.
They do have other concerns that you can see here, and patients don't really like the extra injections and the bone pains that they come with. As I mentioned, for anemia, erythropoietin was used in the past. However, it does have a black box warning now and is no longer used in clinical practice to support chemotherapy-induced anemia. Transfusion is about the only thing that we can do at this point or iron infusions. Obviously, there's infection risk and lately, quite a significant supply limitation for blood transfusions. For thrombocytopenia, there are no FDA-approved drugs for treating thrombocytopenia caused by chemotherapy, and platelet transfusions are the sole source of support for those patients. They tend to be very limited. Transfused platelets last only a couple of days at the most.
It's very common for patients to become transfusion refractory. Just like with red blood cells, there's a limited supply. There's lots of other side effects from chemotherapy, including alopecia, neuropathy, diarrhea, and the fatigue that we just don't have drugs that are effective on. As you can see, there's a pretty significant unmet need in managing chemotherapy-induced toxicities and that some of these can be potentially life-threatening, particularly neutropenia and anemia, as well as thrombocytopenia causing the risk, high risk of bleeding. There are trade-offs, obviously, between higher dose of chemotherapy drugs and avoidance of toxicities, and this sometimes leads to us limiting the effectiveness of chemotherapy in order to reduce toxicity. We also see dose reductions and delays due to toxicity, and then the short and long-term non-life-threatening complications. Innovation oncology treatments really hasn't extended to supportive care.
We've made lots of advances in chemotherapy, but not so much in how we support our patients getting through this, and you can see some of the very few drugs that are currently available. As we note here, there's a lot of room for improvement in supportive care options for cancer patients. This study, the ALRN-6924, is one that we're hoping will make a pretty significant improvement in that. With that, I'd like to thank you all for your time and hand it back to you, Manuel.
Thank you so much, Eric. It's always powerful to be brought back from the highly filtered clinical trial world to the impact of these toxicities in the real world. Before I now transition to an overview of our clinical trials and upcoming catalysts, I wanted to touch just a bit more on the topic of potential regulatory strategies for advancing 6924 broadly to patients with p53- mutated cancer. This slide gives us a 30,000-foot view of the landscape for supportive care drugs over the last three decades, starting with the approval of Neupogen in 1991. I think it's striking to note that nearly all of the drugs approved for supportive care in oncology received a very broad label, as reflected in the sea of green dots on the bottom of the slide.
On this entire timeline, there are only three drugs with a more limited indication. The second thing to note is that until the arrival of the class of cell cycle-arresting drugs, first one being Cosela, every single supportive care drug targeted only one toxicity at a time. Third, from 2006 to 2021, there was virtually no innovation in the supportive care space. As Eric noted, there is a great deal of room for innovation in supportive care. How are we developing 6924? We have generated and continue to generate scientific evidence that demonstrates the reliability of our approach to protect normal healthy cells from chemo. We began with proof of mechanism in bone marrow stem cells. From there, we expanded to gut mucosa cells.
As you heard today from Dr. Paus, we have now expanded our proof of mechanism into hair follicles and their stem cells. We subsequently achieved proof of mechanism in healthy volunteers in bone marrow stem cells. In about a minute, you will get a sneak peek of our latest data, the human proof of mechanism for hair follicle protection after a single dose of 6924. As publicly presented last year at ESMO, we achieved proof of concept for 6924 as chemo protection against clinical toxicities in patients with SCLC undergoing topotecan. Now we have two ongoing randomized trials evaluating 6924 in two new cancer types, NSCLC and breast cancer, with two distinct chemo regimens. As explained today, those two chemos carry very different toxicity profiles.
Based on the data from these trials and our subsequent discussions with the agency, we expect to advance to a pivotal trial, and the goal remains to offer chemo protection for all patients with p53- mutated cancers. Turning to some clinical development details now. As previously guided, we plan to present follow-on findings from our healthy volunteer study at a medical conference in the second half of this year. Today, we want to give you a sneak peek at some of the key new findings we have received from that study. We can confirm now that pharmacodynamic effects showing that 6924 activates p53 to induce P21, and thereby cell cycle arrest, can be demonstrated in serum, in bone marrow stem cells, and in hair follicles. You can imagine how thrilled we are about this strong foundation of data for our mechanism of action.
It is important to keep in mind that all this data is generated in healthy normal cells, which are exactly the same cells we are treating in our cancer trials. That gives us confidence about the probability that we will be able to continue reproducing these effects in our clinical cancer trials, as we demonstrated with our first chemo protection trial in small cell lung cancer patients. This is a good segue to now talk about our two ongoing clinical trials in a little bit more detail. In our NSCLC trial, we will randomize a total of 60 patients with advanced p53- mutated NSCLC who will be scheduled to receive frontline chemo. This trial is double-blind, placebo-controlled. It has open sites in the U.S. and in five European countries.
Patients must, of course, have p53 mutant disease, and patients receive 6924 or placebo the day before, the day of, and the day after chemotherapy. Next month, we're anticipating an interim analysis on 20 patients, and top-line results from all 60 patients should follow in the fourth quarter of this year. Given that our interim analysis of this trial is imminent in June, I want to spend two minutes talking about what to expect from that interim readout. We expect an initial evaluation of the composite endpoint, which is the proportion of chemotherapy cycles that patients remain free of severe side effects, the proportion of cycles that patients didn't need growth factors for neutropenia or platelet transfusions or red blood cell transfusions.
We also expect to report percentages of treatment cycles that were free of the individual components of the composite endpoint, as well as the incidence for the individual components of the composite endpoint. This will be a small n at this point, 10 patients on the treatment arm, 10 patients on placebo. Of course, we won't be reporting statistical significances, but we do expect to see favorable trends that then mature into statistically significant findings as the trial increases to 60 patients. A few things we would anticipate in the top line readout at the end of the year that we do not plan to have at the interim data readout include percentages of treatment cycles free of non-hematologic toxicities, the incidence of non-hematologic toxicities, as well as patient-reported quality of life assessments.
After the interim analysis, we plan to determine whether we'll adjust the protocol endpoints based on the interim findings. This is, let's not forget, a phase I-B exploratory study, and as such, it's wise we learn from initial data to make potential adjustments. Last but not least, one thing not reflected on the slides, but it almost goes without saying. The goal for us, one goal for us here is to get a more clear understanding of the true toxicity profile of carboplatin plus pemetrexed at an AUC level of 6 for carboplatin. Now turning over to the breast cancer trial, which we just announced this morning that we started dosing. This phase I-B trial is anticipated to enroll up to 30 patients with neoadjuvant breast cancer. This is a parallel group designed study with a dose expansion cohort at the back end.
Patients will receive doxorubicin plus cyclophosphamide on day one of each three-week cycle for four cycles. This will be followed by docetaxel given on day one of each three-week cycle for another four cycles. In part one, the dose evaluation, a control group of eight patients with p53 wild type breast cancer will receive chemo without 6924, while patients with p53- mutated breast cancer will be randomized to receive chemo concurrently with our drug, either at 0.3 mg per kg body weight or 0.6 mg per kg body weight. Our drug is given as a one-hour infusion on study days 0, 1, and 2, like in the lung cancer trial. Later, an interim analysis will define the dose for part two, the dose extension.
In part two, 10 patients will receive the same chemo and the 6924 dose that we selected from part one. In closing, we aspire to make chemotherapy safer, and if we do that, we believe we will reduce the number of lives lost from those toxicities, and we will make chemotherapy more effective because more patients will be able to receive or complete chemotherapy, and therefore more lives can be saved. We believe we are the first to show that we do this without inadvertently protecting cancer cells. We have shown the benefits of protecting against bone marrow toxicities in the clinic in cancer patients, and we will now have a chance to evaluate 6924's potential to protect against other toxicities outside of the bone marrow, including hair loss.
As I've described, we aim to generate clinical data to support these expectations in the form of three data readouts this year. Interim data on NSCLC in June, top-line results from NSCLC in the fourth quarter, as well as interim data on breast cancer in the fourth quarter of this year. Thank you for your time. Now I'd like to welcome any questions you might have, which you can submit via the chat function.
Great. Before we start the Q&A session, I would like to remind everyone that you may ask a question using the text box below the video player. With that said, Manuel, your first question comes from Matt Phipps from William Blair. What dose of ALRN-6924 is used in the experiments conducted by Dr. Paus? How do you think the dose needed to prevent bone marrow toxicity compares to the dose needed to prevent K15-positive cell apoptosis?
Thanks for the question, Matt. Truly appreciate it. We made sure that we are operating with relevant doses here. The dose used in the Paus Lab was 1 micromolar, and we reach, even at the lowest dose we're using in the clinic, we reach 2-4 micromolar concentrations in the serum of our patients, and we reach that for several hours. For several hours, we would stay above the dose level that was used in the Paus Lab, which gives us great confidence that we're operating with a relevant exposure in the clinic. We also looked at that question from a cytotoxic perspective, making sure that the paclitaxel concentration used in his study is a relevant dose. I don't know the numbers by heart.
I can follow up with you offline on the exact numbers, but the taxane concentration that was used ex vivo in those experiments in the Paus Lab is actually above, several fold above the concentration of the chemotherapeutic exposure that you would see in cancer patients. Again, giving us certainty that we are operating with very relevant dose levels of both our drug as well as chemotherapy.
Perfect. Your second question is also from Matt Phipps. If paclitaxel-induced permanent alopecia only occurs in about 10% of patients, how difficult will it be to demonstrate clinically or statistically significant differences with treatment of 6924? Is there a validated scoring system for chemotherapy-induced alopecia, permanent or acute?
To start with the first question, to clarify, the current intention is not to elevate alopecia to something like a primary endpoint. The study is not statistically designed or powered to detect a difference in alopecia simply because our focus has been and continues to be to get 6924 approved for hematologic toxicity such as neutropenia, anemia, thrombocytopenia, right? Of course, we are thrilled with the potential to protect against alopecia, something that no drug has ever achieved before, in addition to protecting against all these other non-hematologic toxicities. That would be a big win for us and certainly for patients and for healthcare professionals.
That being said, if one wanted to do a study just dedicated to that, in order to get to a good sample size estimation, we would need to know the effect size. In other words, we would need to know how many patients we're gonna be benefiting in what degree, and that's something that, we will have to learn. Most importantly, probably we'll have to learn from the breast cancer study, where alopecia affects, the vast majority of cancer patients, right? In the lung cancer trial, the alopecia is not gonna be such a frequent side effect. As it relates to the question of, grading systems and scales, that's a great question, Matt. There's not a lot of precedent. Frankly, there's no precedent because no drug has ever been developed to protect against chemo-induced alopecia.
There are so-called cold caps that are FDA-approved, three of them, and one made it to a published randomized controlled trial in which they simply used the NCI CTCAE criteria for the assessment of toxicities in general. In there, alopecia is characterized by two different grades. It's grade one or grade two, grade one being a partial loss of hair, and grade two, all the hair came off, grade zero being no hair loss. For us, we'll have to see the magnitude of the effects of our drug. We're very encouraged by the results we saw today from Dr. Paus and of course, our own exciting data from healthy volunteers. The goal is to avoid hair loss and let's see in how many patients we can achieve that.
Okay. Your next question comes from Soumit Roy from Jones Research. Could you provide us with some color on the components that will be included in the composite score calculation?
Soumit, thanks for that question. The composite primary endpoint is a very important one for us, and the components of this composite primary endpoint are grade 3 for neutropenia, grade 3 for anemia, grade 3 for thrombocytopenia, as well as platelet transfusions, red blood cell transfusions, as well as dose delays and dose reductions of chemotherapy and the use of G-CSF. It's a situation where we can capture multiple different aspects of toxicity and the consequences thereof. Maybe I'll use the opportunity to say a few more words about the interim analysis in the context of which we will be talking about this composite endpoint in great detail. We will be looking at a small number of patients for this interim analysis. It's 10 patients on the 6924 arm plus chemo versus 10 patients on the placebo plus chemo arm.
With that in mind, the goal is that we want to show more cycles on 6924 being administered that are free of many or all of those components of that composite primary endpoint compared to placebo. Now, of course, we also want to continue to see a favorable safety and tolerability profile for 6924, similar to what we have previously presented. Going back to some of the data that Dr. Anderson shared, using carboplatin at AUC 6 is also something that makes this trial so important in order to further inform us about the true toxicity profile of carboplatin in AUC 6 when given in combination with pemetrexed.
I have a few follow-up questions from Soumit Roy. Could you please remind us of the incidence rates and grades of alopecia from the small cell lung cancer trial using 6924 versus placebo?
Yeah. Yeah. Unfortunately, our small cell lung cancer study was in second-line patients, not in front line cancer patients. In second line, the small cell lung cancer patients have come off carboplatin plus etoposide. Etoposide is unfortunately for patients, a hair follicle killer. It wipes out all the hair. Pretty much all patients who came into our small cell lung cancer trial had recently lost their hair from front line treatment. There was no opportunity for us, unfortunately, to test whether or not our drug has an effect on alopecia in the previous clinical trial.
Again, the breast cancer trial that we announced this morning to have started, that is the trial where we are very excited about the prospects of being able to observe potential effects on alopecia when we know that 90% of all women will lose their hair, and importantly, pretty much all of them will lose their hair anywhere between five days after starting chemotherapy all the way to two cycles. It's a very, very quick onset of action that takes chemotherapy to cause hair loss.
Great. We have a follow-up question from Matt Phipps at William Blair. The HV hair follicles biopsy was from 12 hours after the ALRN-6924 treatment. Any reason to think the time course of protection would be any different in hair follicle than bone marrow? Do you have any biopsies from other time points?
Thanks, Matt. Great question, and a very important one. Understanding the kinetics for chemo protection is very important, and it's something that we have dedicated a great deal of time doing. We do not have biopsy data that would give us additional time points in scalp samples from our healthy volunteers. I think what it comes down to is the powerful dosing schedule that we have used. We have created an umbrella of protection over our patients, where we give our drug the day before, the day of, and the day after chemotherapy.
We know with the quick onset of action, we know with the roughly 24-hour duration of the effect, that even if there are some variations in terms of the onset in certain tissues and when the effect has vanished in certain tissues, we think that with this dosing schedule, we create a very powerful umbrella of protection over various different tissues, including the hair follicle. Fingers crossed, that shouldn't be an issue given our dosing schedule.
Great. One follow-up question from Soumit Roy. What percent of patients in first-line non-small cell lung cancer and breast cancer do not complete the full treatment regimen due to safety issues?
Yeah, there's various different data, and the data obviously comes from clinical trials, roughly on average 30%. KEYNOTE-189, for instance, is an example, where up to 30% of patients were not able to complete chemotherapy on dose on schedule, even though there's a very promising treatment available to these patients in frontline non-small cell lung. I think here again, we have to keep in mind some of the words we heard from Dr. Anderson, right? That's 30% in a clinical trial patient population. Taking a step back, we know that in the U.S. in particular, it's only 5%-6% of all cancer patients that make it into a clinical trial. It's a highly filtered patient population.
The real world data will look very different, something that we are actually currently exploring internally. The real world will see a much, much greater number of patients who can actually not complete the four to six cycles of chemotherapy, and a much greater number will not be able to stay on dose without dose reduction or dose delays. Something that I have experienced in my 10 years of clinical experience all the time. It is for an average normal patient with all the comorbidities that they bring, it is quite a burdensome therapy.
Okay. Before we continue to the next question, just want to remind everyone, if you wanna ask a question, you can use the answer box below the video player. Your next question here is from Hunter Rogers at William Blair. In the healthy volunteer studies are study, are scalp biopsies being taken at different time points from the same patient after 6924 treatment or is it similar to how you have done the bone marrow biopsies with different time points for different patients?
Yeah, great technical question. Thanks, Hunter. We kept it aligned with the bone marrow samples. In other words, healthy volunteers only gave one scalp biopsy for one given time point so that the samples are matched. You have a matching skin or scalp biopsy sample matching with the bone marrow sample.
Okay, perfect. Next question. Nobody dies from alopecia, but it's intriguing to see a drug that may remedy chemo-induced hair loss. What does the data mean for you?
That's a great question. It is very true. Nobody's gonna die from hair loss, fortunately. For us, we've always stated that based on the way our drug works, based on its mechanism of action, biologically, there is no reason why our drug wouldn't protect all cells in our body that are dependent on self-renewal and that therefore are the prime point of collateral damage by chemotherapy. Showing now this data in two different settings in the hands of the Paus' lab colleagues with human hairs and showing, for us, showing it in healthy volunteers, who were infused with 6924 with just one infusion of 6924 mind you, nurtures our confidence that what we have stated previously, this hope, this belief that we should be able to see also effects on other toxicities, is on the right path.
When you think about the slide we showed, Hunter, where we have this human being in the middle and we show the toxicities on the left-hand side, we show the hematologic toxicities that can be objectively measured. On the right-hand side, the much more difficult to measure non-hematologic toxicities right where you're dependent on subjective assessments by nurse practitioners and oncologists, right? Much more difficult to ascertain effects on those subjective toxicities. On top of that list stands alopecia, and then it goes all the way down mucositis, nausea, vomiting, fatigue, diarrhea, et cetera. To me personally, this means that we are seeing the first sign that we can tackle the top one on that list and gives me great confidence that we will also see some evidence that we can tackle some of these other toxicities on that list.
Because if we protect one type of cells outside of the bone marrow, well, then that really begs the question why we wouldn't also protect other types of cells outside of the bone marrow. I believe that if we do, then we will truly transform, we will revolutionize supportive care because why wouldn't you, as an oncologist, want to give one drug that can take care of most toxicities instead of giving half a dozen of different drugs, leaving out certain side effects that you cannot remedy today with available medicine. There is no drug approved currently to treat low platelet counts. There is no drug approved to treat hair loss. There's no drug approved to treat fatigue.
We're very encouraged by today's data on alopecia and hope that it's foreshadowing some evidence that we will see other protection outside of the bone marrow as the data matures. Certainly in this setting, in non-small cell lung cancer for the interim analysis, I would temper expectations to see too much on non-hematologic toxicities yet simply because they're not that frequent in a clinical trial setting. Towards the end of the year when we get to the top-line results from all 60 patients, I think it's gonna be very interesting to see what the non-hematologic toxicities will look like comparing the placebo arm to 6924 in such a randomized double-blind placebo-controlled setting as this trial.
Great. Manuel, you just mentioned a little bit about what to expect during the interim analysis. Can you elaborate a little bit more on what you expect to see at the June readout?
Well, we're gonna be looking at a relatively small sample size, right? It's gonna be 10 patients on ALRN-6924 plus chemo, 10 patients on placebo plus chemo. We will be focusing on our composite endpoint, I think, as I covered in the first question on the components of the composite endpoint. We will also be reporting not only the percentage of cycles that were free of those side effects, but we will be also reporting on the percentage of patients who experience these side effects. We will be looking generally at the safety tolerability of our drug, and it's gonna be an important readout for us. We have always stated that in the spirit of this being a phase I-B study, we have to learn from our data.
We have to understand what is the true safety and toxicity profile in these patients in this setting. Giving AUC 6 carboplatin and measuring as frequently as we do using lab data to assess these toxicities. We're not relying here on adverse event reporting, which can be under-reported. Here we're relying on objectively measured lab data, right? All that will tell us how frequent these things are. Then on the active arm, it will tell us what was the magnitude of the effect of our drug on those individual components. The protocol was written in a way that it pre-specified that there is the ability to then make adjustments to the endpoint, as necessary. We will do so if necessary.
Thank you, Manuel. There are no further questions at this time. Manuel, I'll turn it back over to you for closing remarks.
All right. Thank you very much. With this, let me say thank you to everyone. Thank you for joining us this afternoon. We hope you found today's presentation informative. We are very excited about our continued progress to advance 6924 for cancer patients, and we look forward to providing you with more updates in the months ahead. With this, goodbye. Have a good evening.