Fulcrum Therapeutics, Inc. (FULC) Earnings Call Transcript & Summary

Good morning, and thank you for joining Fulcrum Therapeutics Virtual KOL event featuring FTX-6058 for sickle cell disease. I'm Christi Waarich, Director of Investor Relations and Corporate Communications. Just a few words before we get started. This is our disclaimer. Please refer to our most recent filings with the SEC for a discussion of certain risks and uncertainties associated with our business. Before I turn it over to Robert Gould, Fulcrum's President and CEO, I'd like to remind you that today's presentation will be followed by a Q&A session. [Operator Instructions] Thank you again for joining us. I'd now like to turn it over to Robert. Robert?

Thank you, Christi, and thank you, everybody, for joining us on this webinar on our sickle cell disease program. We're very excited to present this program to you today for 2 reasons. First of all, for the potential of our lead compound, FTX-6058, to elevate fetal hemoglobin in patients with sickle cell disease and also patients potentially with beta-thalassemia. Secondly, we're excited because this is a good example of our product engine's capability to not only identify targets that regulate gene expression but also to identify novel small molecules to regulate those targets. Next slide, please. So our vision is to treat genetically defined diseases by addressing their root cause. And today, we'll be presenting an example of elevating a gene to protect against the devastating effects of sickle cell disease. But we also have an exciting program to decrease the toxic protein in a form of muscular dystrophy called FSHD. And both of those are examples of our systematic approach to identify small molecules to rebalance gene expression. Next slide, please. These are products of our FulcrumSeek discovery approach, our discovery engine which utilizes cells derived from patients with either the disease or, in the case of the sickle cell program, healthy individuals. Utilizing our small molecule library and CRISPR approach, we've been able to identify novel targets that elevate fetal hemoglobin. And this information, along with functional profiling, morphological profiling and transcriptional profiling, has enabled us in a short period of time to move into Phase I studies with FTX-6058. Next slide, please. This is an exciting program in our Fulcrum pipeline, where we have a number of programs in clinical development, not only sickle cell disease and potentially beta-thalassemia for hemoglobinopathies but also FSHD and COVID-19 utilizing losmapimod. We also have a number of programs that are at the discovery stage, where we are identifying novel targets to up- or down-regulate genes of interest, utilizing small molecules. And of course, our 2 very exciting partnerships with Acceleron and MyoKardia, focusing on pulmonary disease and cardiomyopathies. And this breadth of coverage of disease areas, I think, illustrates the robustness of our product engine. Next slide, please. So for today's discussion, we're very excited to introduce you to sickle cell disease and beta-thalassemia, significant unmet needs that require novel therapies, and introduce you to an orally bioavailable compound that can elevate fetal hemoglobin and therefore has the potential to provide meaningful clinical benefit. We identified the target EED, which, when inhibited, can elevate fetal hemoglobin. We designed a small molecule, FTX-6058, to elevate that fetal hemoglobin by binding to and inhibiting EED. And multiple preclinical studies have shown robust fetal hemoglobin elevation in cells and genetically engineered sickle cell disease mice. Next slide, please. So just to begin today's agenda, Maureen Achebe will be introducing us to sickle cell disease and the potential benefit of elevating fetal hemoglobin. And I'll have Maureen say a little bit more about her background. We're very excited to have her join us today. She'll be followed by Gerd Blobel, who will introduce us more to the molecular biology of fetal hemoglobin elevation. We'll then continue with presentations from Fulcrum scientists on FTX-6058 and also what we are anticipating our future will be with 6058. So with that, I'll turn it over to Maureen. Maureen?

Good morning. My name is Maureen Achebe. I'm a hematologist at Brigham and Women's Hospital in Boston and I'm the Director of the comprehensive sickle cell center at our institution. I'm pleased to be here and excited to tell you how the physicians see sickle cell disease. In today's talk, I'm going to briefly go over sickle cell disease to sort of orient everyone. And then I will talk briefly on what patients look like with sickle cell disease. I'll talk about the pathophysiology of sickle cell disease. I will talk about what we have currently for treatment. And I'll talk about an unmet need and the benefits or the potential benefits of a small molecule. So what is sickle cell disease? Sickle cell disease is a blood disorder. It's a hereditary blood disorder. So that when a couple carry the trait for each baby, they have a 1-in-4 chance of having a child who has sickle cell disease. Sickle cell disease is the disease of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen to different parts of the body. It has 2 alpha chains and 2 beta chains. The problem with sickle cell disease is a point mutation in the beta-globin gene of hemoglobin. So that instead of the normal sequence of hemoglobin A, which is normal adult hemoglobin, sickle hemoglobin has a mutation on the beta gene at the sixth position with just one amino acid change that causes a significant number of downstream untoward effects. Next slide, please. Under normal circumstances, red blood cells that have sickle hemoglobin behave normally. Now when they go through the vasculature and become deoxygenated, that's where we have a problem. So that the abnormal hemoglobin changes confirmation in such a way that each molecule is able to dock on to neighboring molecule to form these polymers that are abnormal. These polymers of hemoglobin are stiff and they align themselves within the red cell so as to make the red cell look sickle shaped. The picture at the top is normal hemoglobin -- or normal red blood cells. And at the bottom, you see how we see sickle cells under the microscope. We also know that there's a secondary pathophysiology of sickle cell disease. So we've known about the central pathophysiology, which is hemoglobin S polymerization for many years since the 1950s. Now the vasculopathy, which is a secondary effect, we only sort of got smart about in the early 2000s. So that instead of there only to be an abnormality in the red cells, we see that all patients with sickle cell disease also have problems with white cells, with platelets, with the endothelium. That's the vasculature, so the vessels. So that it makes it much more likely that the patient with sickle cell disease will have these clumps of red cells and other cells, will have lack of oxygen to their organs and the consequences of that hypoxia or deoxygenation. Next slide. So how do we see patients? Patients with sickle cell disease are primarily known. So anyone who knows anything about sickle cell disease knows that patients present with pain. They have excruciating pain crises that are spontaneous and can happen anytime, anywhere and is a major dent in their quality of life. Pain can happen in any part of the body. It's what is most responsible for hospitalizations due to sickle cell disease. So this is why we most frequently see patients. But all patients also have fatigue because they are all anemic. Now this is the most visible abnormality in sickle cell disease. But we also know that sickle cell disease causes significant injury to all the vessels -- all the organs of the body. Next, click the next slide. In the cardiovascular and thoracic system, so in the heart and lungs, it causes something called acute chest syndrome, which can lead to kidney -- sorry, lung failure. In the brain, it can cause strokes both for kids and for adults. In the reticuloendothelial system, it leads to sort of death or ischemia to the spleen and so they're prone to infections. Next slide. In the musculoskeletal system, it leads to necrosis, which is bone death, death of bones. It can cause kidney failure and it can cause many other things, including gallstones early in age. Next slide. So in the U.S. -- well, in the world, there are over 300,000 babies born with sickle cell disease per annum. Most of them are born outside the U.S. In the U.S., there are 90,000 people with sickle cell disease currently. The advances that we've made in therapy so far have led to a significant number of patients going from childhood and surviving into adulthood. So more than 95% of children with sickle cell disease will reach adulthood in the U.S. So compared to -- the graph on the right shows the life expectancy for patients with sickle cell disease over decades. In the 1970s, the life expectancy for a patient with sickle cell disease in the U.S. was 10 years. Now our life expectancy is somewhere in the 50s. We've made a significant stride in making that -- in pushing that forward. But when you compare it to this -- the graph in blue, which is the average life expectancy for all Americans, you see that we really still have a long way to go. Next slide. So we see the pathophysiology of sickle cell disease now much more complex than we thought of it before. So besides the hemoglobin polymerization, which is a central pathophysiology, there are all these other secondary effects that cause morbidity and mortality in patients with sickle cell disease. Next click. These -- but now that we have -- now that we know more about the pathophysiology, it has also led to more investigation of novel therapeutics. So the mainstay of therapy is hydroxyurea. And I'll talk a little bit more about hydroxyurea. FDA approved in 1998 after a multicenter trial that was published in the New England Journal of Medicine in 1995. And then it took about 20 years later for L-glutamine to be approved and that was in 2017. L-glutamine balances the oxidative milieu of the red cells. Now last November, within 10 days of one another, we had 2 therapies approved: voxelotor, which also acts on a hemoglobin polymerization and crizanlizumab, which targets vasculopathy. So it's a P-selectin inhibitor that targets vasculopathy. And then we still -- we have gene therapy, which is new, and stem cell transplant, which isn't that new but is ongoing. Next slide. So let's talk a little bit about hydroxyurea. So hydroxyurea was first investigated on its ability to induce fetal hemoglobin. So we see induction of fetal hemoglobin as fundamental advantage. There are natural history studies of patients who have sickle cell disease and coincidentally have hereditary persistence of fetal hemoglobin. And these patients are -- or people are asymptomatic. We know exactly how fetal hemoglobin does this. So if you remember the schema I showed you earlier on the left showing polymerization of abnormal sickle hemoglobin, we know that in order for polymers to form, you need that abnormal valine at the sixth position of beta-globin but you also need an acceptor site. And that acceptor site is on sickle hemoglobin. It's on regular hemoglobin, too, but that site is sort of lacking or is altered in fetal hemoglobin. So both adult and sickle hemoglobin have threonine at position 87, while fetal hemoglobin, which is different because it has a gamma-globin gene, has glutamine in its place. And that changes or disrupts polymerization significantly. Next click on the next slide. So what do we have now for therapy? We have hydroxyurea, which we've had since 1998. It decreases polymerization. It causes fetal hemoglobin increases, not in a uniform way but that -- but it's effective in doing that in some patients more than others. And in doing that, it's able to increase hemoglobin, decrease pain crisis. It's oral and affordable. And the main disadvantages are that it is inconsistently effective in adults mostly and we don't know the reasons for that. So it's able to induce fetal hemoglobin in some adults and not others. Because it's chemotherapy, it is also myelosuppressive. So it suppresses the bone marrow. And so some patients get so much bone marrow suppression that they're unable to use hydroxyurea. And therefore, we don't have those patients on hydroxyurea. More recently, as I said before, we have glutamine. It balances the also oxidative stress on the red cell. And the goal is really to decrease hemolysis or early breakdown of red cells. It's oral therapy so it's somewhat affordable. The problem is that patients need to take 15 grams of L-glutamine a day. So it's a powder rather than a pill because there's so much. And so that leads to noncompliance. More recently, we have crizanlizumab, which works on vasculopathy. It is -- it was approved to decrease pain crisis. It's a monthly administration. So that's an advantage. The disadvantage is that it's intravenous. So patients need to be tethered to some institution where they get infusions once a month. And obviously, it's expensive. And then voxelotor. Voxelotor decreases polymerization by increasing oxygen affinity of hemoglobin. It increases the hemoglobin of patients. The benefit of that is it's an oral therapy. The disadvantages are that it's somewhat pricey. And we are -- but it was just approved. So we're watching to see how well it does on the market. Then we have stem cell therapy and gene therapy. So both of these require some bone marrow suppression. For stem cell therapy, I think our biggest drawback was finding matched donors for patients. Gene therapy affords the potential of a cure. But of course, because there's chemotherapy, there are problems with its causing infertility. It is extremely expensive and therefore will not be the solution for most people who have sickle cell disease. We can go to the next slide. So although we have all -- we are actually quite excited about the new therapies we have most recently. And we think most -- it has been enhanced. The ability for there to be more going on in this space has been enhanced by our knowing more about the pathophysiology. But patients -- we still have patients in the hospital very frequently. Patients are in the emergency room or in the hospital. And when they're in the hospital, it's not a short stay. On average, it's 5 days but it's often much longer. You can imagine -- most of us have never been to an emergency room. But patients get -- I mean the emergency room staff know patients because of how frequently they need to be in the emergency room, some of these leading to hospitalizations and some not. And then when patients are in the hospital, it's not a fun stay. It's not a fun stay for a patient and it's not a gratifying stay for the physicians either because all we're doing is trying to relieve pain. And we are quite often unable to do that in any way that would be acceptable. Next slide. So what would we say we need now. We really need oral therapies. Ideally, one that would be used once a day, one that's safe, one that's effective, one that inhibits hemoglobin S polymerization since we know that is the central pathophysiology of sickle cell disease. We know that we can get there if we find an agent that will induce fetal hemoglobin in a pancellular way. And we know that because we have natural history studies that show us that induction of fetal hemoglobin can actually make people asymptomatic with normal life expectancy. In order for this new compound to be safe, you would have to have minimal off-target effects, at least that's how we see it. We assume that if there are many off-target effects, there will be more symptoms. We would - oral therapies will be better tolerated by patients than intravenous therapies. So that they can go about their lives, not necessarily needing to visit a hospital setting or infusion setting, either once a month or more frequently. And oral therapies have historically been more affordable than others. So we think that what we would -- what patients will benefit most from would be oral therapy. We think that an oral therapy is likely to be used in combination with other therapies. Knowing how many things are the matter with sickle cell disease, we think that, ultimately, we may need to treat sickle cell disease the way hypertension and diabetes are being treated with more than one therapy. And some patients will benefit from one therapy more than others. Thank you.

Thank you, Maureen. That was a very nice overview. Next, we'll be hearing from Dr. Gerd Blobel, who will be describing mechanisms that can be -- have been identified and could be pursued to elevate fetal hemoglobin. So next slide. So Gerd, I'll let you take over from here.

Yes. Good morning. My name is Gerd Blobel. I'm at Children's Hospital of Philadelphia, where I run a lab, where we study molecular biology of globin gene expression to a large part. And I'm also the Co-Director of the UPenn Epigenetics Institute. So Maureen summarized very nicely why we're here. If you can also forward this to -- click one more time, please. There are 2 diseases that are really multi-system disorders that both benefit from elevated fetal hemoglobin levels. Now sickle cell disease -- all patients with sickle cell disease have the same mutation. Thalassemia, however, is much more complicated. There are various degrees of disease severity, depending on the type of mutations that patients have. And this is a case of thalassemia intermedia that I'm showing here. Many forms, not all of them but many forms of thalassemia would benefit from elevated fetal hemoglobin expression. Next slide, please. So this is an older study, but I think it impressively illustrates the effects of elevated fetal hemoglobin levels, in this case on patient survival, and Maureen has touched on this already. And this, of course, has been studied since the '90s in much greater depth. And we have now much better numbers of what we need in terms of fetal hemoglobin levels to be of therapeutic benefit. But I think it's important to take away from this slide that you don't have to be necessarily achieving curative levels of fetal hemoglobin. You can elevate fetal hemoglobin levels and have a much improved outcome even if patients are not cured. So there is great benefit to elevating fetal hemoglobin levels even if we may not be able in every patient to achieve the threshold levels that people have thrown around typically. Next slide, please. So the evidence that fetal hemoglobin levels are beneficial is supported by many lines of evidence. First of all, we noticed from very strong genetic studies. For example, there's a benign condition called HPFH or hereditary persistence of fetal hemoglobin. In this benign condition, individuals make fetal hemoglobin throughout their adult life. And these individuals are perfectly normal. They oftentimes don't even know that they have this condition. However, if you co-inherit a mutation that leads to HPFH, as a sickle cell patient, your clinical course of the disease is much, much improved. So that's very strong evidence that fetal hemoglobin levels are beneficial. And this is, of course, further supported by patients who respond to fetal hemoglobin inducers just like hydroxyurea as Maureen just mentioned. Next slide. So I'm going to very briefly get a little bit nerdy and tell you a little bit about the mechanism of globin gene expression. So the globin genes are arranged on the chromosome in the order in which they're expressed through our development. So we have embryonic, fetal and adult forms. So the fetal form of hemoglobin is produced when our red blood cells are formed in the fetal liver. And they are silenced after birth when our red blood cells are mostly formed than in the bone marrow. And so that makes -- that explains why diseases affect the beta-globin gene, the adult forms of beta-globin like sickle cell disease and some form of thalassemia, why these diseases manifest themselves after birth. And so the goal has been for many, many years in the field to try to understand the molecular foundation of this switch from fetal to adult globin genes. But the goal, of course, is to reverse the switch. Next slide, please. So as Maureen was just saying already, there are -- and you've seen this in the news. Actually, this morning driving in here to my office, there was a long report on NPR about follow-up on sickle cell patients that had undergone gene therapy. And so there are many different ways by which people try to elevate fetal hemoglobin expression. For example, in the left-hand panel, there are clinical trials going on where people simply try to make a lot of fetal hemoglobin, in this case, called gamma-globin, the gamma-globin chain or the anti-sickling form of beta-globin that Maureen mentioned. There's now -- of course, in the age of CRISPR, there are ways now where people have succeeded in trying to generate mutations that affect regulators of fetal hemoglobin such as BCL11A or trying not to attempt using gene editing to correct these mutations. There's also attempt to knock down fetal globin repressors such as BCL11A by hairpins. This is also in the clinic. You've seen it in the news. And there's other experimental approaches on the way. And as Maureen was saying, while these therapies are potentially curative, they all require autologous bone marrow transplant with bone marrow conditioning, which basically amounts to a very harsh form of chemotherapy, of which there, of course, are long-term risks, short-term and long-term risks. And of course, this is extremely costly. It can only be carried out at very sophisticated medical centers at this time. So there is clearly a need, next slide, please, for the development of small molecules that can be developed into drugs, that can be applied easily, cost effectively and to a broad number of patients in the United States and abroad. I mean I think that's a critical consideration. You can -- if you take a pill, you can stop taking it. When you've undergone gene therapy and the gene therapy may have not worked or may have long-term consequences, it's much harder to reverse those effects. Next slide, please. So I'm going to say 1 or 2 more things about the basic science. And then I'm going to get a little bit more about the specific compounds we're discussing here today. So there are 2 major molecules that are direct repressors of the fetal globin genes. They're called BCL11A and LRF. They sit directly at those genes and help keeping them silent. And there's genetic evidence from naturally occurring HPFH mutation that support this notion. Now of course, like all other -- first of all, these are transcription factors. They bind DNA and they're inherently difficult to target with small molecules. But we know that these transcription factors don't work on their own, right? They have accomplices. They recruit other molecules that help them keep these genes, the fetal globin genes, silent. And this includes a NuRD complex, for example, and many other regulators, epigenetic regulators. In this case, I'm referring to regulators that affect these fetal globin silencing functions. And here's just an example if you move on to the next slide, please. This is from an older study from Jian Xu when he was in Stuart Orkin's lab. And if you advance the slide, this is -- this basically is -- was an educated guess-type experiment based on also some biochemical data that screened several tissue-specific or general regulators, potential regulators of fetal globin expression. And what I highlight here is general co-repressors. These are all molecules that are implicated in fetal hemoglobin silencing. So when you deplete them, you can raise gamma-globin expression or fetal globin expression, which is on the X axis. And if you forward the slide, there are 2 components of the PRC, also called polycomb complexes. Very strong, and they are in the top 10 of general co-regulators that are involved in fetal globin silencing. Next slide, please. And here's just an example from a study from Dan Bauer's lab at Harvard, who has demonstrated that a general co-regulator or co-repressor, in this case, the component of a NuRD complex, which is a co-repressor for BCL11A and LRF is also an effective silencer of fetal hemoglobin expression. So I'm just making this point really that general factors can be really important regulators of fetal hemoglobin silencing even though they're not restricted in their expression to red blood cells or that they are restricted even to the globin genes. They can be doing other things. But they may have functions if you dial them down just the right -- to the right level that you can have a very beneficial effect on fetal hemoglobin induction. And that, of course, includes these PRC2 molecules. Next slide, please. So we've carried out CRISPR screens, genetic screens and human erythroid cells to identify regulators of fetal hemoglobin silencing or even also activation. And next slide, please. And again, we discovered a transcription factor that then imparts regulation on this NuRD subunit, CHD4. And again, I'm using this as an example, how general factors can be really, really important. So ZNF410 is a general factor that's important in silencing of fetal hemoglobin expression through this unique pathway by targeting a general co-regulator. But it's a transcription factor and we can target it very easily. And we don't have small molecules against it. Okay? Next slide, please. And I should say that just like the work that I've shown you earlier from Jian Xu and Stuart Orkin, our screens as well as the screens that you hear about from Fulcrum have also identified several PRC2 components as fetal hemoglobin regulators. And this is critical because I think it provides independent validation of these polycomb group proteins, that's what they're also called, as targets and as key regulators of fetal hemoglobin expression. Okay. So on to next slide, please. So what are the key validation standards in the field? What are sort of the benchmarks that people typically have to meet and hurdles to clear when moving a target forward? So the first thing, of course, is when we and others and Fulcrum have carried out screens in human erythroid cell lines such as HUDEP2, you want to validate these targets by using individual guide RNAs. The next step, of course, is that you validate your targets using independent knockdowns, perhaps independent guide RNAs in primary human tissue cultures from normal individuals or from sickle cell disease patient as donors. And then typically, the next step is using mouse models. So mouse models are -- they're famous mouse models. They're called the Townes model or the Berkeley mouse model, in which mice are engineered to express human-type globin genes. The NBSGW mice are xenotransplant models, where you transplant human stem and progenitor cells into mice and they support erythropoiesis up to a point, at least in the bone marrow. And you can use those to assay your therapy of choice. I should say that the Townes and BERK transgenic -- human transgenic mouse models are very strict or very vigorous models in the sense that mice are very good in turning off human fetal globin genes. They're actually better in silencing human fetal globin genes than human cells are in a tissue culture dish, when you put humans cells in a dish like point number two. And they are easier -- the fetal globin genes are easier to reactivate or to reawaken compared to this mouse model. So these mouse models are rigorous and oftentimes used in many different studies, pharmacologic studies and gene editing or modification studies. Next slide, please. So here are some critical questions that people interested in this space might ask. And I've touched upon on this first question already a little bit, but does it make sense to drug a widely expressed protein such as these polycomb group proteins or also PRC-type proteins? I'm using these terms interchangeably. And there's plenty of examples in the literature, of course, and in the clinic now also, not just under experimental settings. We have general molecules that function in a general fashion across tissues or across genes, such as histone deacetylases or BETs, which are chromatin, metaproteins or many protein kinases that have broad functions. But if you dial them down, you might get beneficial effect that affect a certain type of tissue or a certain type of cancer that's especially impressively shown by BET inhibitors, for example. Okay? Next slide, please. So do beneficial effects have to be direct? And as I was saying, BCL11A and LRF are these 2 direct repressors of fetal globin expression. But so far, there is no small molecule out there that can target these factors. So we're sort of left with the task of trying to target fetal globin steps by indirect mechanisms. And I would say that hydroxyurea that Maureen had described nicely, which is a fetal globin inducer, it's not super potent, it doesn't work in all patients. And -- but we still -- after all these years, we don't really know exactly how it works. It might work by multiple mechanisms but the effects are very likely indirect. And that same is -- the same holds true for other experimental fetal globin inducers that have been described in literature, such as pomalidomide, G9a inhibitors, azacytidine or in the early days, short-chain fatty acids. So no, it doesn't have to be a direct effect to be effective in raising fetal hemoglobin expressions. Next slide. A key question also is whether one should expect that one single molecule, one compound or one drug can do it all and be curative? Of course, that's what everybody is striving for. And any lead compounds, any drugs like PRC inhibitors can ultimately perhaps be improved and modified to be a single compound treatment. But even if that's not achievable, maybe right now in the short term, there could still be great beneficial effects by using HbF inducers, fetal globin inducers even if they have partial effect size. And that is illustrated here in this cartoon here, where one can say that perhaps combinations of drugs that elevate fetal hemoglobin levels, for example, hydroxyurea plus a polycomb inhibitor or PRC inhibitor might have additive or even synergistic effects in raising fetal globin levels and thereby increase the therapeutic index. We might even be able to lower the concentration of each drug when used alone and still achieve desirable effects and minimize off-target effect. So this is illustrated here. You can have compound A and compound B. They each have a partial effect. You put them together and you may have cooperative or even synergistic effects in fetal globin induction. Next slide, please. Of course, there could be other ways by which drugs can synergize from a clinical perspective. So if we are taking if we're just ignoring fetal hemoglobin levels for a moment, one could argue that if you have a compound -- one of the compounds or one of the drugs that Maureen described that reduces, for example, the propensity of sickle cells to adhere to the vascular endothelium, and you combine that with a fetal globin inducer, you may have overall clinical benefits by reduced VOCs, for example, or any other criteria that you use even though they work by completely independent mechanisms. So drug combinations converging on entirely different mechanisms might still provide cooperative patient benefits. Okay? Next slide. Yes. So another question that I think is oftentimes asked, do we have to know the exact mechanism of action? And it's pretty clear that -- I mean it's wonderful if you have a perfect target. If you have BCL11A, that makes a wonderful target for gene therapy. And that's why it's been used for gene therapy approaches. But we don't have a drug for it. But there are many other co-regulators, some of which I've described to you, that have been implicated in fetal globin silencing where we don't know the exact mechanism of action. That is true for several of the other experimental fetal hemoglobin inducers. So here, I will just argue that even when the molecular targets of a drug are known, everything that happens downstream may not be entirely clear yet. But that should not stop us from using an empirical approach to test and forward compounds if they have beneficial effects such as fetal globin induction or other beneficial effects for patients with sickle cell disease. Okay? I think that's an important consideration. And so with that, I think if you want to move on to the last slide, I want to thank you for your attention and I look forward to the question session. Thank you.

Thank you, Gerd. Next, we're going to have Owen Wallace introduce us to FTX-6058. Next slide, please. And hopefully, what Owen will convince you of is that FTX-6058, this novel HbF-inducing agent, has real potential for the treatment of sickle cell disease and beta-thalassemia through its direct -- through its effects on elevating fetal hemoglobin. Owen?

Thank you, Robert. As Doctors Achebe and Blobel have already indicated, there's a significant potential for the activation of fetal hemoglobin in the treatment of sickle cell disease and even relatively modest increases have the potential to reduce mortality, reduce recurring events such as VOCs and, if the levels are high enough, even result in potential asymptomatic presentation of the disease. And we believe this approach is also amenable to beta-thalassemia and to other anemias. 6058 is now in Phase I clinical studies. We identified the target from our product engine and developed a potent and selective EED inhibitor that we believe has the potential for oral once-a-day dosing. And we anticipate being able to deliver plasma exposures that can elevate HbF in the clinic based on our preclinical models. And we're very excited about the preclinical data that I'll share with you today. And our composition of matter IP patent has published and issued in November. We discovered a variety of targets that can activate fetal hemoglobin from our product engine. We used a combination of both CRISPR screens and our proprietary small molecule probe screening collection in addition to computational biology, which resulted in several targets that we've heard about today, including BCL11A and the NuRD complex, we chose to target EED for the up-regulation of fetal hemoglobin. We used a structure-based drug design approach to develop 6058. And this is a potent and selective EED inhibitor. It has a clean off-target profile based on our preclinical data. And as I noted, our composition of matter IP issued in November. EED is a component of the PRC2 complex. As we've just heard about, PRC2 catalyzes the trimethylation of histone 3 at lysine 27 or H3K27. And this is a repressive signaling -- silencing signal. EED is a component of PRC2 and it binds specifically to existing H3K27 trimethyl marks and helps to propagate the spreading and signaling of the H3K27, resulting in increased transcriptional repression. Our compound binds directly to EED. And this results in a decrease in the spreading of this repressive H3K27 trimethyl mark, resulting in activation of the gene. I'll share with you some of our robust preclinical data in the coming slides, where we've profiled both the quantity and quality of HbF induction. And just to orient you, I'll be sharing a variety of different parameters. The first one is looking at whole blood parameters. Here, we're looking at the percentage of fetal hemoglobin and this is measured by HPLC. We're also looking at the distribution and pancellularity of HbF expression. And as we've heard, this is a critical component in an effective therapeutic. Here, we're measuring the percent of cells that express measurable fetal hemoglobin and we do this by flow cytometry. And we're also looking at intracell measures of fetal hemoglobin activation. And we do this by looking at the individual globin chains using mass spectrometry. This slide shows some comparative pharmacology data of FTX-6058 across our in-vitro models relative to other mechanisms that have been reported to increase fetal hemoglobin. In the first column, you can see the data for HUDEP progenitor cells. In red is the curve for HbF elevation and in black is total hemoglobin levels. And you can see a very robust impact on HbF. As we now moved into primary cells, CD34 positive cells from healthy donors, again, we can see a robust elevation using HPLC of HbF and a pancellular distribution. We're seeing almost 90% of the cells expressing fetal hemoglobin. And this HbF enrichment can be seen over on the right-hand side, looking at the flow cytometry trace, which clearly indicates an increased number of cells expressing HbF relative to the vehicle control in the top row. As a comparison, a DNMT1 inhibitor or a G9a inhibitor appears to have a very narrow therapeutic index in vitro. While we do see an increase in fetal hemoglobin, we see a rapid decrease and also a decrease in total hemoglobin, which we attribute to cell toxicity. In our hands a PDE9 inhibitor failed to have robust elevation of fetal hemoglobin either in the HUDEP2 progenitor cells or in the CD34 positive cells. We looked across a variety of other mechanisms as shown in the left-hand panel in this slide. And the conclusion is similar to the one that I just shared. So with these mechanisms, either we saw indications of cell toxicity or, in many cases, we fail to see robust elevation of HbF. On the right-hand side of the slide, we're now looking at the pharmacological inhibition of EED relative to a genetic knockdown of EED or BCL11A, the repressive complex that Gerd just mentioned. And as you can see with FTX-6058 shown in the dark gray, we're seeing a robust elevation of HbF that's very similar to the genetic knockdown of EED and also quite similar to the genetic knockdown of BCL11A, which we think is a very encouraging profile for a small molecule. We profiled FTX-6058 across multiple human donor cell lines, both healthy donor cell lines and sickle cell disease donor lines. You can see in the plot here that every single cell line was responsive. And we saw between an 8% and 18% increase in total fetal hemoglobin levels on treatment with 6058. And if this were to translate into a clinical study, this could have a very meaningful impact on the lives of patients with sickle cell disease as shown on the right-hand part of this slide. And we believe that this profile phenocopies hereditary persistence of fetal hemoglobin as we've already heard about. We then profiled 6058 across human donor cell lines that we characterized as either nonresponsive to hydroxyurea, responsive to hydroxyurea or partially responsive to hydroxyurea. And you can see the hydroxyurea response for each of these cell lines highlighted in the orange rectangles. In all cases, we see a robust elevation of fetal hemoglobin as shown in the blue bars with FTX-6058, indicating there might be a potential even in nonresponsive cell lines. We then took these same 3 cell lines, the nonresponsive, responsive and partially responsive cell lines, and combined an EED inhibitor with hydroxyurea. This is a close analog of 6058 called 6274. And once again, by combining hydroxyurea with the EED inhibitor, we're able to see an increase in the expression of fetal hemoglobin. And this suggests that an EED inhibitor such as 6274 or 6058 potentially has the opportunity to sensitize these cell lines now that they are responsive to hydroxyurea, again, a profile that we think is really very encouraging. Now moving to some in-vivo pharmacology. This is in the sickle cell disease Townes mouse model that Dr. Blobel just referred to. As anticipated over on the left-hand part of the slide, we see robust EED target engagement with FTX-6058 as measured by the H3K27 trimethyl mark. We also didn't anticipate to see any target engagement with hydroxyurea or a PDE9 inhibitor, which is exactly what we saw. With this robust level of target engagement, we see an increase in F cells, as shown in the middle panel with 6058, and a concomitant increase in the protein as measured by HPLC. Interestingly, even though we see maximum target engagement with 6058, we still maintain around 30% of the H3K27 trimethyl mark. So this is not the same as at EED knockout, for example. We then profiled much more broadly various different hematological parameters in the sickle cell Townes mouse model. And these parameters, we believe, are potentially relevant in the treatment of sickle cell disease. Just to orient you along the X axis of each of these plots is the percent elevation of fetal hemoglobin. And the vehicle control shown in the open circles, hydroxyurea in the gray circles and PDE9 inhibitor in red, all seem to cluster together in these plots. But with 6058 treatment, you can clearly see a differentiation here. And although the experiment was not powered to see statistical significance across all of these parameters, I think you'll note that we see very encouraging trends. For example, the increase in F cell in the top left, we showed you some of that data already, an increase in red blood cell count shown in the middle at the top, hemoglobin at the right and the lower panel, we see a decrease in reticulocytes, a decrease in white blood cells and a decrease in neutrophils. Again, we think, a very encouraging profile. Over on the right-hand part of the slide, we show the effect on spleen weight. And splenomegaly is an issue with sickle cell disease patients. And we see this recapitulated in the sickle cell mice shown in the gray bar, which clearly differentiates relative to the nonsickle cell disease control mice. On treatment with 6058 in the lower part of the panel, we can see a significant decrease in spleen waste, whereas we didn't see any significant effect with hydroxyurea or the PDE9 inhibitor with this particular study. We then looked at the durability of response of 6058 in the Townes mouse model. In this particular study, we dosed daily for 28 days and then ceased dosing but monitored the hematological parameters following the cessation of dosing. And here in the red, you can see the elevation of fetal hemoglobin following 28 days of dosing. 4 days later, we see those levels maintained, whereas 7 days after termination of dosing, the levels start to decrease. And by the time we're out to 12 days, we're returning close to baseline levels. And this profile is very consistent, not just with the mechanism of action but also the red blood cell half-life, where we know that cells expressing fetal hemoglobin have a longer half-life both in mice and in humans relative to their sickle counterparts. So we're really encouraged by the preclinical data across our numerous models. We've profiled in multiple human donor lines, HUDEP2 progenitor cells, healthy CD34 positive cell lines and CD34 positive lines from sickle cell disease donors. We've also shown an elevation in embryonic globin in wild-type mice and, as I've shown you, the fetal hemoglobin in sickle Townes mice. Consistently across all of these models, we see a two to threefold elevation of fetal hemoglobin. And we believe that if this robust effect was translated into a clinical study, it would provide very meaningful impact to individuals with sickle cell disease and beta-thalassemia. As I noted, our Phase I clinical study in healthy volunteers is ongoing. We are currently in the single ascending dose part of the study, where we anticipate looking at doses between 2 and 90 milligrams. Our multiple ascending dose cohorts are anticipated to go from 2 to 20 milligrams. And based on our PK/PD modeling, we anticipate that the pharmacological doses will be in the 6 to 20 milligram range, where we should be able to achieve high levels of target engagement, including up to maximum levels of target engagement and potentially strong induction of fetal hemoglobin. Interestingly and notably, again, we don't anticipate that even at these high levels of target engagement that we'll see complete repression of the H3K27 trimethyl mark. And we anticipate that we would see about 30% of this mark remaining. We anticipate sharing more of our clinical data in mid-2021 and also initiating our trial in patients with sickle cell disease next year. In addition, we're advancing our clinical strategy for use in patients in beta-thalassemia. In terms of regulatory considerations, we are very enthusiastic that the FDA appears to be open to the use of a surrogate end point reasonably likely to predict clinical benefit in sickle cell disease. And we intend to continue our dialogue with the FDA and other health authorities as the program progresses. And as the data warrants, we intend to seek orphan drug designation, fast track and breakthrough therapy designations. So to summarize, we're really enthusiastic about the potential for 6058 to have an impact on hemoglobinopathies such as sickle cell and beta-thalassemia. We identified EED from our product engine and developed a very attractive EED inhibitor that we believe will be an oral, once-a-day potential therapy with a very impressive pharmacological profile based on our preclinical data. The composition of matter has issued. And we're actively dosing healthy volunteers currently. And if this robust and consistent two to threefold induction in HbF that we've seen preclinically did translate into the clinical population, we believe this would be a very meaningful therapy for sickle cell disease patients.

Thanks, Owen. So with that, we'll now have Bryan Stuart, our Chief Operating Officer, discuss with you how we see FTX-6058 fitting into the overall paradigm of sickle cell disease and beta-thalassemia treatment. Bryan?

Thank you, Robert. So while considered an orphan disease, sickle cell disease is actually very prevalent globally and very well diagnosed. So as Dr. Achebe mentioned, we'll speak to some of the prevalence and incidence numbers but over 100,000 patients in the U.S., 50,000 patients in Europe and millions more worldwide. So this truly is a global disease. And as we focus just more on the U.S. market, there's been extremely robust prenatal screening. Patients are getting diagnosed at very high rates. And as a company like Fulcrum then thinks about developing therapies, enrolling trials, recruiting, there is a relatively concentrated group of patients throughout the country which facilitates our ability to do this and to progress through the clinic. And as we think about 6058, we think it truly has the potential to be uniquely positioned as a best-in-class treatment for sickle cell disease. And this is based on all of the very well-known benefits of inducing fetal hemoglobin that you heard about from Dr. Achebe, Dr. Blobel and from the Fulcrum team. So we think 6058 has the opportunity to really exist at an intersection of 3 very important criteria for patients and physicians: one, efficacy; two, safety and tolerability; and three, convenient dosing. So from an efficacy perspective, what's very important about inducing fetal hemoglobin and about the potential of 6058 is that 6058 has the potential to address both anemia and VOC-driven disease. And we think that's going to play a very important role in where 6058 can fit into the treatment paradigm. Also, as you learned about earlier today, hydroxyurea has very meaningful safety and tolerability issues. Some of the gene therapies that are being developed have very rigorous pre-treatment regimens that are going to limit when and how they're being utilized. So we also believe that having a convenient oral dosing is going to be extremely important to patients. This is a very large patient population, as we mentioned, on a worldwide basis. And oral therapy is really truly what patients need. Now focusing a little bit more on the treatment paradigm. So we spoke about some of the limitations with hydroxyurea. While most patients are prescribed hydroxyurea today, very few can stay on therapy due to the safety and tolerability issues as well as some of the efficacy shortcomings. So a lot of what is approved, and there have been some recent approvals, are focused on either the VOC or the anemia-focused disease. And then additionally, the cell and gene therapy area is getting more crowded with more approaches in that space. But a novel fetal hemoglobin inducer, we believe, has the potential to be the cornerstone of therapy. And this is due to the ability to affect both aspects of the disease and just all of the benefits inherent in inducing fetal hemoglobin. And as we look towards what is being developed, well, there are a lot of programs entering the clinic. The majority of them are focused either on anemia-driven disease or VOC-driven disease or the gene and cell therapy area, which is getting more crowded. But there is still this tremendous need for a first-line treatment and that is for a small molecule that has the potential to induce fetal hemoglobin. So the positioning that we see for 6058, both in the near term and the long term, we believe has the potential to be very transformative for these patients. One of the other reasons that we're so enthusiastic about the target ANDA approach is that inducing fetal hemoglobin not only has the potential to benefit patients with sickle cell disease but also with beta-thalassemia. And that is an area that we at Fulcrum are continuing to focus on when it comes to clinical development. And as we look to advance 6058 for sickle cell disease and now being in Phase I as we are, our focus is now going towards beta-thal and working through how we can advance that in the clinic as well. So to summarize and some of the things that we discussed today, we believe that sickle cell disease and beta-thal are an area with tremendous unmet need and FTX-6058 with this very robust data that we've been able to show preclinically truly has an opportunity to be a transformative therapy for patients. And despite some of the recent innovations in sickle cell and in beta-thal, the unmet need still remains very meaningful. You heard that from Dr. Achebe today. You hear that from other KOLs in this space that patients need more therapies, physicians need more treatment options. And what they're really seeking is a small molecule that can induce fetal hemoglobin. The orally bioavailable compound that we have in 6058 is one that we're extremely encouraged by for the applicability in both sickle cell disease and beta-thal. This approach came out of our product engine. And I think as Owen spoke to, what we're extremely enthusiastic about is the consistency. So as we've looked at this program preclinically, we've looked at it in CD34s. We've looked at it in the Townes model. We've seen this very consistent induction of fetal hemoglobin. We've seen a very consistent increase in F cells. And this pancellular approach, we believe it really has -- it gives us the opportunity to essentially phenocopy this hereditary persistence of fetal hemoglobin. And in sickle cell disease, we have these very clear benefits of inducing fetal hemoglobin. And we believe it's a very clear surrogate that can provide clinical benefit. Also, we believe oral dosing is an extremely important attribute. We spoke about the size of the patient population. We spoke about the unmet need that exists today. And an oral, once-daily convenient dosing is very important to physicians as they think about future treatments. And we are actively enrolling, as we mentioned, in our Phase I right now, continuing with SAD and MAD. We anticipate being able to share data from that in the middle of next year and then quickly advancing into sickle cell patients. So we plan on doing that in 2021 and also, as we mentioned, advancing our clinical development strategy for beta-thalassemia which we also see as a very exciting opportunity for this program. With that, I'll turn it back over to Robert.

Thanks, Bryan, and thank you all for your attention. This time, we'll be very happy to take any questions that you might have, either on the clinical need for an elevator of fetal hemoglobin, the advantages of an oral molecule or some of the specific characteristics of FTX-6058. I'd ask that you use your chat function and direct your questions to Christi Waarich. And then I'll direct to the most appropriate person to answer your questions. So with that, we'll open it up for questions.

Great. So our first question is how do we ultimately see FTX-6058 being combined with other sickle cell disease agents.

Yes. So maybe we'll start with Owen reviewing again the combination data that we saw with hydroxyurea and then have Bryan recap how we see it fitting in the overall clinical paradigm.

Yes. We're really excited about the potential to combine 6058 with other mechanisms. Hydroxyurea is obviously a cornerstone of current treatment. And as you'll remember from our data, we have the potential to increase the elevation of fetal hemoglobin by combining 6058 with hydroxyurea. We think that's a very interesting profile. I think the other interesting data is that there's a potential perhaps to treat with 6058 individuals who are nonresponsive, at least in our cell lines. We clearly could elevate fetal hemoglobin in cell lines that were not responsive to hydroxyurea. And just to go back to Dr. Blobel's discussion around combinations, in addition to fetal hemoglobin elevation, we think that this is a very complementary mechanism to go on top of others that are in development already or even commercialized. So we don't see that fetal hemoglobin elevator would be in any way incompatible with the current treatments.

Great, Owen. Bryan, do you want to expand a little bit more on how we see the combination with anemia-driven disease and VOC-driven disease?

Yes. So I think we very much -- as Owen mentioned, we view a small molecule, fetal hemoglobin inducer, as really being the cornerstone of therapy. I think one of the things that we're enthusiastic about is as we look at other agents being developed for anemia or VOC-driven disease, we think there's the potential for combination with those patients where that would be relevant or beneficial. But I think in terms of fetal hemoglobin in the very well-understood benefits of being able to affect so many different attributes of the disease, we think this is going to be really a potential cornerstone therapy.

Thank you.

Great. And our next question is what did we see in terms of dose-limiting talks in animals. And could you speak a bit about the FDA's guidance on tox coverage and how this has informed our clinical plans?

Owen?

Yes. We're not disclosing the specific details of the toxicology studies. But we have completed 28-day GLP tox studies, both in rodents and in dog. And we're very encouraged by the profile. We believe that we've got a sufficient therapeutic index to be able to dose up to those doses that I shared in the SAD and the MAD. And based on all of our preclinical data, those doses should be ones that affect pharmacology, ones that engage the targets and are predicted to increase fetal hemoglobin. In terms of FDA guidance, they came out with a document about 18 months or 2 years or so ago to suggest that for diseases like sickle cell disease, there may be an opportunity to dose longer. In humans, then the tox coverage would typically support. So typically, a 1-month tox study nonclinically would allow for 1 month of dosing in the clinic. There may be an opportunity with 1 month of preclinical toxicology to actually support a 3-month human study. So we're obviously going to continue profiling in longer-term tox studies. And we believe they'll be important as we move into longer-term human studies as well.

And I would just remind the listeners that we are anticipating based on our preclinical studies to get full target engagement, 100% target engagement, at the 10 to 20 milligram dose. And of course, the Phase I protocol that we agreed with the FDA gives us the opportunity to go as high as 90 milligrams. Dr. Achebe, maybe you could speak to what kind of questions you get from your patients as you educate them and talk to them about some of the newer therapies that are coming along.

Yes. So patients are, in general, pretty excited about new therapies. They hadn't been in new therapy for a long time. So that wasn't really a discussion we had in the clinic until recently. So they are enthusiastic, actually more enthusiastic than I would have predicted about participating in trials, seeing whether we can get new drugs approved for sickle cell disease that either they or people in their families will benefit from. So I think they are -- we certainly do need therapies. That's for sure because we are -- we populate the emergency room a lot and we're on admission for weeks at a time. So definitely -- they definitely would be anxious to have new therapies that are effective and are supportive, at least in theory, of more things being on the market.

I may jump in here as well. So we had a town hall meeting at Children's Hospital of Philadelphia about 1.5 years ago, where patients, their families, met with doctors and scientists. And I was amazed, there was a room full -- a large room full of people, how enthusiastic and how interested and how educated the patients were about new developments and new treatments and their willingness to try new things because it gave them hope for their families. So this was not a scientific study but the enthusiasm was extraordinarily high.

Yes. Thank you. Christi, are there other questions that we can speak to?

Great. Yes. I'm just compiling them here. So another question is do you have -- do we have gene expression array data when the drug is applied to demonstrate the specificity of the target.

Owen?

Yes. I'm certainly happy to have Chris, our Senior VP of Research, also comment on this. We've profiled in several different cell lines from human donors both erythrocytes and other cells, such as neurons, cardiomyocytes, myotubes, et cetera. And we're currently analyzing that data. But most of the gene expression changes that we see are in erythrocytes, which is what we would expect, with relatively few changes observed in the other cell types. But Chris?

There's nothing more for me. That's exactly right. Very specific effects within the CD34 erythrocytes and no significant effects on gene expression in the 3 cell types you mentioned.

I think that's one of the characteristics of our product engine that we've really begun to appreciate is our ability to look at the effects of small molecules, regulating gene expression across multiple differentiated human cell types, the cardiomyocytes, skeletal myotubes, erythrocyte progenitors, neurons. Christi?

Great. Yes. So another one. So how might preclinical results seen in sickle cell disease models translate to beta-thalassemia? And what other preclinical work might be necessary to increase confidence in FTX-6058 in beta-thalassemia and move into the clinic?

Yes. Maybe I'll take a first stab at that and then let Owen or Bryan or Chris expand on it. Just like there's a relationship between the amount of fetal hemoglobin and the remuneration of clinical symptoms in sickle cell disease, there's also a relationship between the amount of fetal hemoglobin and benefit in beta-thalassemia patients who were clearly more fetal hemoglobin is associated with symptomatic relief in the beta-thalassemia patients. At this point, we don't believe that there's a large amount of preclinical data that's necessary to move forward into beta-thalassemia patients. Our current plan is to verify clinical proof-of-concept that we are, in fact, elevating fetal hemoglobin in the sickle cell patients. And then as we expand on that observation, consider how we will move into beta-thalassemia patients very quickly following that. But Bryan or others?

No. I think we would just add that inducing fetal hemoglobin in beta-thalassemia has a very clear and well-understood benefit. So our focus right now in addition to advancing 6058 is the clinical strategy involved in getting into a clinical study in beta-thal. And that's a big focus of Fulcrum.

Great. So we have another question. What other genes are regulated by EED? And what other genes should we be mindful of as 6058 progresses in the clinic? That's the first part. And then there's another question for Dr. Achebe. For clinicians, is HbF induction significant on its own? Or would you need accompanying VOC reduction data?

Maybe I'll take that -- I'd like Dr. Achebe to take that second question. And then I'll have Chris speak to the first question, the effect of EED on gene expression.

Okay. So we -- if there is a pancellular induction of fetal hemoglobin that's robust, it's -- there is a potential that we will not need other therapy because polymerization is the central pathophysiology. And we think vasculopathy is secondary to hemoglobin S polymerization. The question is whether we can get that much induction. Patients with HPFH or the hereditary persistence of fetal hemoglobin have up to 30% of pancellular distribution of fetal hemoglobin. So if we were to get that, that may be all we need. If we don't get that, we expect to get some benefit. So we don't need 30% to gain any benefit but we expect to get some benefit from induction of fetal hemoglobin. But then we may need other therapies to improve patient outcome.

And just before Chris speaks to the other point around gene expression, I just want to reemphasize that the hereditary persistence of fetal hemoglobin in patients with the sickle cell gene really provides, we think, convincing and strong human genetic evidence that -- as Maureen has said, that as we elevate fetal hemoglobin itself with a single agent like FTX-6058, that has real potential to provide meaningful benefit to those patients. And that's why we're positioning FTX-6058 as a stand-alone agent in our initial clinical -- will be in our initial clinical studies. This is really an exciting approach to a single agent opportunity to phenocopy the fetal -- hereditary persistence of fetal hemoglobin that human genetics has taught us so much about. Chris, maybe you want to talk to the gene expression effects.

Sure. So we are very much in the midst of analyzing the gene expression data that we've generated but also, as Gerd alluded to, trying to understand the connection from inhibition of EED and PRC2 and the relative intermediary effector pathways that are modified and gene expression networks that are modified that lead to an increase in fetal hemoglobin expression. So we're very much in the middle of that. And I think as we begin to look at that data and have a story to tell in terms of how we can connect those dots, we'll be looking forward to sharing that data at the appropriate time.

Maybe it's also worth mentioning that elevation of fetal hemoglobin does have very little downside on its own. I mean like I said earlier, like Maureen was saying, individuals working around this 30% that is more fetal hemoglobin and they don't know they have the condition. They can give birth to normal children and they are perfectly functioning individuals. So there's really very little downside to elevated fetal hemoglobin expression, which is why it makes it such an attractive target.

Great. So another one. There's been some discussion around increases in HbF as being potentially an accelerated approval end point. This has been parameterized as change in percent HbF and some have suggested 3% might be viable. Is this the right parameter?

Yes. We think sort of 2 parts to that question. We think, certainly, in a disease as complicated as sickle cell, as Maureen emphasized for us, the paucity of orally bioavailable, widely available therapies in this disease with the devastating effect on people's lives as well as on the health care system creates the opportunity for potentially accelerated approval. And certainly, others have discussed their regulatory interactions towards that end. I think the amount of fetal hemoglobin that's necessary, as we've been looking at it, we're excited about the two to threefold or 200% to 300% increase that we're seeing in fetal hemoglobin as we go forward and the opportunity we think we have to move fetal hemoglobin into these really important ranges of sort of the 10% to 30% range. FTX-6058 on its own in every model that we've looked at, the 3 different human systems as well as the mouse systems that Owen described for you has consistently and robustly elevated fetal hemoglobin up into the percent levels that the hereditary persistence of fetal hemoglobin teaches us is important for disease. So we're excited about the opportunity. We think fetal hemoglobin is an important parameter. And we think that based on our preclinical data, we have a stand-alone agent that has the potential to move fetal hemoglobin into those levels. And that will provide obviously the basis for discussion with the FDA on their view of those elevations in fetal hemoglobin to lead to clinical meaningful outcomes.

Great. Another one for Dr. Achebe. The Albert Einstein group has presented data that the protective effect of hereditary persistence of fetal hemoglobin may wane as a function of time and with adults having less benefit than the pediatric population. That was just the question, if you could comment on that.

I think what the -- what they may be referring to is -- I'm not sure I understand that waning with -- the hereditary persistence of fetal hemoglobin waning over time. I guess patients who have HPFH maintain those fetal hemoglobin levels for life. If they are referring to induction of fetal hemoglobin, I may have spoken to it briefly in my talk. There is more success inducing fetal hemoglobin in kids. So when kids are started on hydroxyurea, they almost universally are able to induce fetal hemoglobin. And the same is not true for adults. We think that, that is partly because of the chronic effects of having sickle cell disease in the bone marrow prior to initiation of hydroxyurea. So what we see is that the bone marrows in adults, and this is not universal, but for some adults unable to tolerate -- or their bone marrows are unable to tolerate hydroxyurea doses that are required to induce fetal hemoglobin. You know that the induction of fetal hemoglobin, at least to some extent, is dependent on stress erythropoiesis. So it suppresses the bone marrow. And in the bone marrow continuing erythropoiesis despite the pressure of hydroxyurea, more fetal hemoglobin is developed. And in adults, we see that the bone marrow suppression that's required for stress erythropoiesis is not tolerated. So they have the reticulocyte counts go down. So in initiating a bone marrow suppressant in adults -- we think that's why adults don't tolerate hydroxyurea. And therefore, I mean I think that can be extrapolated to saying that we're not able to induce fetal hemoglobin in adults as reliably as they are in pediatrics. I hope that sort of answers the question.

Thanks, Maureen. Christi, are there other questions?

There are a few more. Let's see. So one of the -- some of these are similar. So one of the questions is what read-through will we get from the healthy volunteer study into patients if there's any read-through from the Phase I healthy volunteer study into patients.

Yes. The Phase I study, like every healthy volunteer Phase I study, is designed to evaluate the safety, tolerability and pharmacokinetics of FTX-6058. We're looking to move into sickle cells as quickly as possible because we think that's where we'll see an effect on fetal hemoglobin more quickly. Because of the mechanism of 6058, we do need to wait for red cells to turn over. And in healthy volunteers, that turnover is on the order of 90 days, give or take, whereas in sickle cell patients, because of the destruction of the red cells and the stimulus that, that gives to generating more red cells, the red cells turn over much more quickly. So our clinical strategy is to move as quickly as we can to a safe, tolerable dose of 6058 to confirm our projection that this will be a once-daily, orally bioavailable drug in the healthy volunteers, obviously assess safety and tolerability and then move into sickle cell patients as quickly as possible, again, where we think we'll see an efficacy signal more quickly.

Maybe I'll fill the void for a moment. I mean sickle cell patients oftentimes, as you've seen also from the data presented earlier by the Fulcrum team, they have higher levels of fetal hemoglobin already at baseline. And sometimes, we find that also in-vitro cultures, they may be more responsive to pharmacologic inducers. That's why I think that supports what Robert was just saying.

Christi?

Yes. So we're just -- so we have one here. Have you considered evaluation of weight-based dosing in your clinical trials?

We don't think -- believe that we need to do weight-based dosing in our clinical trials. I think the consistency, at least in the preclinical studies of the pharmacokinetic, the oral bioavailability, the drug metabolism effects are robust as well as the reproducibility of the target engagement and the projections that we reviewed for you that we think around -- we'll get full target engagement in the 6 to 10 milligram dose. Again, because of the preclinical tolerability, there's no reason to speculate that we'd need to do weight-adjusted dosing. I think we have about 2 or 3 more minutes, Christi, if the timing is accurate.

Yes.

So as Christi is just looking for -- at the last questions, I just want to reemphasize how excited we are about the potential of FTX-6058 to be a stand-alone, orally bioavailable therapy for these patients that are dramatically in need for new therapies. We think that the elevations that we're seeing in fetal hemoglobin of consistently two to threefold or 200% to 300% as you go across multiple different test systems is exciting. The durability that we see is in the Townes model is exciting for us. And we're really encouraged by the interactions we've had to date with the FDA in affirming the doses that we've selected, starting at 2 milligrams and going up to 90 milligrams orally. We're excited and look forward to, in fact, our projections, that this is a once-a-day, orally bioavailable agent holds up and moving as quickly as we possibly can into sickle cell patients. We anticipate finishing of Phase I in the healthy volunteer studies mid next year. And we'll certainly keep you all informed as we proceed. So I just wanted to finish by thanking Gerd and Maureen for their participation in this discussion today, for their thoughtful accounting of not only the patient needs but the excitement around elevating fetal hemoglobin and our approach to elevating fetal hemoglobin, which came out of our product engine but is confirmed by independent studies and other labs that blocking EED has the potential to be a potent and powerful inducer of fetal hemoglobin. So with that, I'll thank the audience's attention and encourage you all to follow up with us if you have additional questions. You can contact Christi Waarich at [email protected] if you have additional questions. Thank you.