Good afternoon, everyone, and thank you for joining the 2025 HC Wainwright 27th Annual Global Investment Conference. I'm Dr. Jade Montgomery, an Associate Biotech Research Analyst at the firm, and I'd like you to please join me in welcoming from Fulcrum Therapeutics, Alex Sapir, President and CEO, and Dr. Iain Fraser, SVP Head of Early Development. Alex?
Thanks so much, Jay, and thank you all for joining us. Why don't we jump right into it? Obviously, over the next 20 minutes, I will be making certain forward-looking statements, and I would encourage you to review the full list of our risks and uncertainties in our public filing documents with the SEC. I'll use my laser pointer. Unfortunately, the people that are online won't be able to see this, but maybe just to start, the company's focus since its inception has always been somewhat differentiated, and that was to really use small molecule technology to modify gene expression in rare diseases where there continued to be a high unmet need. We feel that using small molecule technology is more elegant, more scalable, and it has broad applicability compared to maybe some of the more recent cell/gene therapies. Those efforts have now been proven successful.
We have a product called Posiradir. It is what we believe to be a best-in-class small molecule for the treatment of sickle cell disease. It has been granted both fast track as well as orphan designation. We just recently put out some data in July of this year, which I'll be spending some time walking through with all of you. In addition to that, we also have a very robust discovery pipeline, which I'll share in just a minute, as well as a very robust cash balance sheet of $214 million as of the end of Q2, which gives us a runway into 2028. We run very, very, very lean and very operationally efficient. Here is our pipeline. I'll spend the bulk of my time talking about Posiradir, again, an oral small molecule for the treatment of sickle cell disease.
In addition to that, we also have some very, very interesting discovery efforts. Probably the latest of those discovery efforts is for a group of diseases called bone marrow failure syndromes. These constitute a number of bone marrow failure syndromes, all of which symptomatically result in very severe anemia. We'll be filing our first IND for that drug that we believe has the potential to treat a number of these bone marrow failure syndromes, for which these patients have currently no treatment options. We'll be talking a lot more about that in 2026 and beyond. Let's really focus our attention on Posiradir. Posiradir is used in the treatment of patients with sickle cell disease. This just gives you an idea of how large this market is.
Globally, there's about 7.7 million patients worldwide that suffer from sickle cell disease, about 100,000 patients in the U.S., and about 55,000 patients in Europe and the UK. It is driven by an abnormal sickle-shaped red blood cell, which essentially results in a shortened lifespan for these patients. The number one symptom that sickle cell patients experience are these severe, debilitating pain crises. Sickle cell patients experience essentially constant pain 365 days a year, but occasionally throughout the year, for an average patient, maybe three or four times, these pain crises become so debilitating that they wind up becoming hospitalized. Unfortunately, the road for sickle cell patients, I would say over the last five years, has been one of fits and starts. I think there was a lot of excitement and promise beginning in 2019 with the approval of two therapies, one called Adakveo, the other one called Oxbryta.
Then about four years later, you saw the approval of not one, but two cell/gene therapies for the treatment of sickle cell. Unfortunately, Adakveo failed to confirm a benefit in reducing these VOCs, these very painful, debilitating crises, and that drug was subsequently pulled from Europe and has some utilization, although relatively lackluster utilization, here in the U.S., even though it continues to be approved here in the U.S. This other drug that I mentioned, Oxbryta or voxelotor, unfortunately, was pulled from the market in 2024 due to an imbalance of these VOCs from the active arm to the placebo arm.
Even though you've seen the cell/gene therapies be commercially available for about one to two years, their uptake has been somewhat limited, primarily because of the risks, the costs associated with these cell/gene therapies, not to mention some of the operational challenges for the patient of needing to be hospitalized for, you know, upwards of four to five months as they're undergoing that procedure. Unfortunately, the reality today is that these patients continue to experience a high burden of these vaso-occlusive crises or VOCs that wind up them becoming hospitalized. There are certainly access barriers for gene therapies, and just overall a lack of broadly and effective durable therapies for this patient population. That's really where Posiradir comes into play. Maybe just a minute or two about how Posiradir was discovered.
It was discovered through our own internal discovery efforts using a very robust CRISPR and compound screening engine that was proprietary to Fulcrum. Essentially, what Posiradir does is it is a PRC2 inhibitor. It binds to the EED subunit of this PRC2 complex, and by doing so, it will, in a very robust fashion, increase the protein fetal hemoglobin. Now, why is fetal hemoglobin important for these patients? I think this slide does a very nice job of explaining this. Fetal hemoglobin is critical for these patients in terms of reducing these vaso-occlusive crises. There's a tremendous amount of data out there that shows that as you increase fetal hemoglobin, you see a subsequent decrease in VOCs. I articulate that really in two different sets of data. On the left-hand side here, this is data that was presented at ASH last year.
What it showed is that for every 1% increase in fetal hemoglobin, you saw a 4% to 8% reduction in VOCs. If a patient saw their fetal hemoglobin levels increase by 6%, you're essentially seeing a 25% to a 50% reduction in vaso-occlusive crises, which we know is considered clinically meaningful by the FDA based on previously approved agents. This data here that you see on the right-hand side is data that we pulled from a real-world data set of about 700 patients. We're actually going to be presenting this data in just a couple of weeks at the ASCET conference where we have an oral presentation. Essentially, what this data shows is on the left, on the x-axis, you have percent fetal hemoglobin, and on the y-axis, you have the percent of patients that were vaso-occlusive crisis-free during that given year.
What I really want to call your attention to is this sort of middle range here as you go from the high teens to the mid-20s. Why don't we just take the 15% mark here. As you can see, if you can get a patient's fetal hemoglobin levels up to 15%, you essentially have about, call it 89% to 90% of those patients that are VOC-free. You can see that highlighted here in this very short table down at the bottom of this slide. If patients go from 15% to 20%, you see an additional sort of 5% of patients who are VOC-free. Once you get to 25%, these patients are essentially functionally cured.
Essentially, the promise for this drug is to be able to use small molecule technology, which has been our origin since our early beginnings, to modify gene expression to essentially bring what would be a functional cure for these patients. Being able to do that with a once-daily oral small molecule would really be transformative to these patients compared to the more intensive cell/gene therapies. What really excited us about this program early on was some work that we did in healthy volunteers. Now, on the y-axis here, you're not looking at the fetal hemoglobin protein, but you're looking at the HBG mRNA. As you see here, for these healthy volunteer patients that were dosed the drug in a very dose-dependent manner, 2 milligrams, 6 milligrams, 10, 20, and 30, at day 14, you saw a very, very elegant dose response in this HBG mRNA as patients increased their dose.
That got us really excited to advance into patients as quickly as possible. This is the study that we are currently enrolling in. It is a phase 1B open-label study. At the end of each cohort, we're able to essentially present that data to all of you. The data that I really want to focus on right now is this 12 milligram data, 16 patients that we recently completed and read out as of the end of July. Here was the demographics of the patient population, fairly evenly split between men and women. About 60% of the patients were U.S., 30% were from South Africa. Very severe patients. These patients, on average, had either about three VOCs during a six-month period of time prior to enrollment in the study or five VOCs during the previous 12 months.
I ask you to really keep in mind those numbers because we're going to come back to those numbers in just a minute. Baseline fetal hemoglobin levels for these patients were 7.6%. Again, our goal with this drug is to try to get those patients' HBF levels higher compared to where they are today at 7.6%. Let's take a look at the data. This is, here's your 7.6% here. This is your baseline. At the end of that three months, we saw our fetal hemoglobin levels essentially, which started at 7.6%, increased to 16.2% or an absolute increase of 8.6 percentage points of fetal hemoglobin. The next question is, okay, how did each one of these patients perform? This is what you see here, on this graph. The gray here was the patient's fetal hemoglobin level that they had at the start of the study.
The blue part of this bar chart is the absolute % increase that they experienced over those 12 weeks. Remember what I showed you earlier, that if you can get patients to a 20% fetal hemoglobin level, you're seeing about a 90 to 95% reduction in VOCs. If you notice here, we, in essence, were able to get almost half. Seven of the 16 patients at the end of that study had a fetal hemoglobin level at the end of that 12 weeks of greater than 20%. Really, really exciting for these patients.
What's also really important, and I just want to spend a minute on this, is you can increase your fetal hemoglobin, but if that fetal hemoglobin is only being concentrated in a small number of red blood cells, it won't be as beneficial to the patient compared to increases in fetal hemoglobin levels that happen across many of the red blood cells, i.e., sort of pancellularity. What this data shows is that at the start of the study, the presence of fetal hemoglobin existed in about 34% of all the red blood cells. By the end of that study, we were able to show essentially a doubling of the red blood cells that had the presence of fetal hemoglobin. What's important is that the medical community believes that once you get to 70%, that's essentially pancellular.
That's in essence what physicians that treat, that will ultimately prescribe this drug, that's essentially what they're looking for for their patient. The fact that we saw a doubling and got very, very close to that 70%, which again is considered pancellular by many physicians that treat patients, that also got us very excited. I think the other important point to make is that six of the patients actually did achieve levels of fetal hemoglobin, the presence of fetal hemoglobin in greater than 70% of those red blood cells. Again, really, really excellent data. The other thing that you would expect to see is as you're increasing your fetal hemoglobin, you should see less hemolysis or destruction or rupturing of these red blood cells. What we look for is we look for some of these markers of hemolysis to see if those markers are going down.
There are four markers of hemolysis: LDH, bilirubin, reticulocyte count, and red cell distribution width. As you can see, across all four of those markers of hemolysis, we were seeing a decrease, in essence, sort of indicating that you are causing less hemolysis. If you are causing less hemolysis, you should see total hemoglobin go up as well. We saw a reduction in LDH. We saw a 37% decrease in bilirubin. We saw a 30% decrease in reticulocyte counts. We saw about a 30% decrease in the width of the red blood cell. What you would hope then is you would see a corresponding increase in total hemoglobin. As you're causing less of these red blood cells to hemolyze or to rupture, you should see a corresponding increase in fetal hemoglobin.
As we all know, the more hemoglobin we have, the less anemic we are, the better we feel, the less fatigue. That's exactly what we saw in this study. Patients started with a baseline, again, total hemoglobin, not fetal, but total hemoglobin of seven grams per deciliter. By the end of the study, we saw almost a one gram per, we saw almost a one gram per deciliter increase in fetal hemoglobin and total hemoglobin at the end of that study at 0.9. Remember I talked a little earlier about the correlation between increases in fetal hemoglobin and reduction in VOCs. This was a very, very short study, only three months in duration, but the data that we saw on VOCs left us very encouraged. Here are those baseline numbers that I shared with you earlier that I asked you to keep in mind.
These patients would have expected to have about one and a quarter VOCs per patient over that three-month period of time. What we observed is essentially a 50% reduction in that expected number of VOCs. We saw essentially nine VOCs across 16 patients during that three months of the study, or about half VOC per patient. What also got us even more excited was the fact that 50% of these patients, all of which had a large number of VOCs prior to coming into the study, 50% of those patients reported no VOCs during the course of that 12-week study. Because of this drug's relatively strong on-target or weak off-target profile, we would also expect to see a relatively benign AE profile. That's exactly what we saw. Very, very well-tolerated drug. A lot of numbers here. This is on our corporate website.
What I will call your attention to is that of the 16 patients, three patients reported a treatment-related AE, three, all of which were considered grade one in nature. This was diarrhea, headache, rhinorrhea. All of those patients, sorry, all of those AEs resolved during the treatment period. Patients did not have to discontinue drug in order for those to resolve. Just to wrap up, as we started this program several years ago, we had an ideal product profile in mind. Ideally, we wanted a drug that would be once a day with a favorable tolerability profile, a drug that could, in a very robust and rapid fashion, increase fetal hemoglobin, be able to do that in a pancellular way. In addition to that, reduce some of these markers of hemolysis and subsequently increase total hemoglobin and thus reduce anemia.
Ideally, a drug that could also reduce these very severe and debilitating VOC crises that these patients experience, which wind them up in the hospitals for several days on end. Based on the data that I just showed you, we're very, very encouraged of the fact that the product profile that we had for this drug and what we were able to achieve in these 16 patients essentially check all five of those boxes. Where we are today is we are dosing in the next cohort. This is a 20 milligram cohort. The data that I just showed you was a 12 milligram cohort. We'll be dosing in a 20 milligram cohort. As of July 25, we had six patients enrolled. We're targeting roughly and approximately 10 patients for this cohort. We should have that data to share with all of you by year-end.
Once we have that data, we will be taking this information back to the agency as part of a very sort of robust end of phase 1B meeting to discuss the initiation of the next study, which potentially could be a registrational study for this very severe patient population. With that, we are right, wow, we are right at zero. That was not done intentionally, but that's pretty good. I think we've got a little bit of time for questions.