Good afternoon, everyone. My name is Ted Tenthoff. I'm a managing director and senior biotech analyst at Piper Sandler. And I understand it looks like box lunches are being served, so if you want to grab one and come in and join us, feel free. Before I begin, I must draw your attention to certain disclosures regarding the relationship between Piper and Fulcrum that are posted in the back of the room and also at the registration desk. So Fulcrum is conducting the phase 1-B PIONEER study of pociredir, formerly FTX-6058, in sickle cell disease patients. Here from Fulcrum today is President and CEO Alex Sapir, also SVP of Early Development, Iain Fraser. Thanks, guys, for being with us.
Yeah, thanks for having us, Ted, and thank you all for your interest in Fulcrum.
So a lot has changed over the last year in the sickle cell disease field. We saw Vertex and CRISPR gain approval for the first-ever gene editing therapy, CASGEVY. Pfizer withdrew OXBRYTA from the market. Perhaps you guys can start off with sort of an overview or a state of the industry. How do you see the treatment of sickle cell disease changing, and what is the remaining unmet clinical needs?
Yeah, it's an excellent question, and a lot has changed, and I think to really start, you really do have to go back really five years ago, and I think that the promise for patients with sickle cell disease was great, and unfortunately, that promise has not materialized, so in November of 2019, we saw the approval of OXBRYTA and ADAKVEO from Pfizer and Novartis, respectively. Unfortunately, OXBRYTA has now been withdrawn from the market, and ADAKVEO, which had the promise to be a billion-dollar drug, is operating right now at about a $200 million run rate. About 1,000 patients are on ADAKVEO, so those new therapies that got approved roughly five years ago have not materialized. Almost four years to the day later, you saw Vertex, CRISPR, and Bluebird cell and gene therapies get approved about a year ago.
And while I think they did hold and do hold great promise for patients because of those products' ability to get fetal hemoglobin levels north of the mid to high 20s, and we'll come back to why that is so important, unfortunately, I think because of the cost, the complexity, and the risk associated with full myeloablation, those therapies, while they do hold great promise, I think will really be relegated to a very, very small percentage of the patients. And we're seeing that sort of, we're seeing that materialize today. So, where the field is, I think, moving towards is really a renewed interest in fetal hemoglobin as a very, very strong biomarker to predict clinical outcomes for patients. I think the unmet need is still very, very high, Ted.
I mean, even though you've seen the advent of many of these newer therapies, they've either been withdrawn for the market or they're being relegated to a very, very small percentage of the patients, and so I think because of that, the 100,000 patients that currently exist in the U.S. with sickle cell disease, not to mention the 4.4 million patients globally, I think the unmet need is still very, very high because this is a disease that still continues to have very high mortality, in which patients are probably surviving 30 years less than the average adult.
Clear quality of life issues, too.
100%.
So that's great perspective. So with that background, please describe pociredir. What is the target, and how does it impact fetal hemoglobin?
Yeah, so pociredir is a PRC2 inhibitor, and by inhibiting the PRC2 mechanism, we're able to show increases in fetal hemoglobin, and we've been able to demonstrate that in a number of patients, in total of about 15 patients, in a very dose-dependent manner, that after only six weeks of dosing, we can very rapidly increase patients' levels of fetal hemoglobin. I think two things to leave you with: any increase in fetal hemoglobin is beneficial for the patients, but once you get above a fetal hemoglobin level in the sort of mid to high 20s, you're seeing a profound impact on patient survival and patient VOCs, as you mentioned, these vaso-occlusive crises that are sort of described by the patients as these excruciating pain crises that essentially wind them up in the hospital.
Essentially, what pociredir has been able to demonstrate as a PRC2 inhibitor is to increase levels of fetal hemoglobin that could potentially be transformative for patients.
Maybe even taking a half a step back, why is fetal hemoglobin so important in these patients kind of to work around the mutation that we're seeing in the [baby]?
Sure, yeah, great question.
Maybe you guys can describe why that mechanism is working.
Yeah, yeah, absolutely. You know, in sickle cell disease, there are these abnormal globin chains that when oxygen tension decreases, they form rigid molecules within the cell. And instead of a nice deformable red blood cell that can [take] its way through the circulation, you have these rigid cells that are more prone to break open. They have a shortened lifespan. That's the hemolysis, but they also can block up the circulation. And fetal hemoglobin, which is made earlier on in our lives, and remember that all newborns are born with 85+% plus fetal hemoglobin in their red cells. So all of us, whether you have sickle cell disease or not, have experienced that at some point in our lives. And then gradually, that gets replaced by the more adult forms of hemoglobin in the first year of life.
But what we know is that patients who have sickle cell disease and who co-inherit the gene that causes that fetal hemoglobin to persist longer than usual have a much milder clinical course of their sickle cell disease. That's really the first observation that was made. And you know, the fetal hemoglobin is sort of diluting out the effect, if you like, of the sickle hemoglobin in the cell and preventing that formation of those rigid globin molecules that cause the disease. So that's the first piece that we know of why fetal hemoglobin is important in these patients. We also know from pharmacological data with hydroxyurea, which has been around for several decades now, that induces fetal hemoglobin in the cells, that patients who have an increase in fetal hemoglobin have decreased mortality and have improved symptomatology. The manifestations of the disease are much reduced.
That's the second strand of evidence that supports the fetal hemoglobin. Then much more recently, with the approval of gene editing therapies, as you mentioned earlier, particularly Vertex CRISPR, which knocks down BCL11A, which is a key regulator of fetal hemoglobin suppression, they're seeing induction of fetal hemoglobin in the red cells of those patients and a dramatic reduction in the manifestations of disease. Multiple strands of evidence, a little bit about the biology of it, and that's the reason why fetal hemoglobin has such a central role in this disease.
Iain, to the extent you're willing to go into this, building on what Alex was talking about, what is the mechanism of pociredir to actually drive that?
Yeah, so the PRC2 complex, which is the immediate target of pociredir, which Alex mentioned, is a histone methylation enzyme. And so it puts methyl groups on histones, and by doing that, it changes the compaction of the DNA within the nucleus, and that regulates gene expression. So if you inhibit that methylation from occurring, you alter the gene expression profile because you've changed the chromatin conformation within those cells. And it so happens that when you inhibit PRC2 by pociredir, that fetal hemoglobin is one of the most highly upregulated genes in response to that. So that's a fortuitous finding that has significant therapeutic application.
And is there any risk for what else is upregulated? And we'll kind of touch on this as we get into the clinical.
Yeah, so it's actually interesting if you look. It's not like there are thousands of genes that are upregulated in that setting. It's in the tens to maybe hundred genes that are some are up and some are downregulated. And if you look at the nature of those genes, there are no red flags or concerns in terms of either the individual genes or the pathways that are modulated by that. So there's nothing in that process in and of itself that has raised any red flags to us.
Now, Alex, you started to touch on this, but maybe you can walk us through in more detail the phase I-B data that you guys have reported. And why did the FDA place a clinical hold on pociredir back in February of 2023, over a few months ago?
Correct. Yeah, so maybe I'll touch on the data that we generated today, where we are with the study now that we're off clinical hold. Maybe I'll let Iain touch a little bit on the details as to why the clinical hold was put into effect, so prior to the initiation of the hold, we had enrolled 15 patients in the study across three different dosing cohorts: 2 mg, 6 mg, 12 mg. And in a very, very, very nice, elegant dose-dependent manner, we saw increasing levels of fetal hemoglobin as you increase the dose. There were several patients in the 12 mg cohort after only six weeks of dosing. We were seeing about an absolute increase in patients' percent fetal hemoglobin of about 10%, so patients were starting at 10% or 15%, and then we're seeing increases of 20%-25% after only six weeks of dosing.
We did have a small hiatus of about six months where we were placed on clinical hold. The clinical hold has been lifted, and so where we are now with the study is we are re-enrolling patients in a 12 mg cohort. In addition to that, we'll be enrolling patients in a 20 mg cohort, 10 patients each, and I think based on the data that we've been able to see today, we're quite optimistic that we will be able to see fetal hemoglobin levels that essentially can replicate what's been seen in the cell and gene therapies, but be able to do that with a once-daily oral, and so that's particularly exciting. We will have data to share with everybody in 2025.
I think as we get closer to 2025, we'll be a little bit more specific in terms of when in 2025 we'll have the 12 mg data to share, followed by the results of the 20 mg cohort, 10 patients each. Do you want to maybe just touch a little bit on the rationale for the hold?
Yeah, absolutely. And maybe first and foremost to say there were no clinical data with pociredir that drove the clinical hold. The clinical hold was based on two strands of evidence. The one piece was related to findings in a subset of the toxicological studies that had been conducted with pociredir, and those findings were some animals developing hematological malignancies in those studies. And then the other strand that FDA brought to our attention that they were obviously aware of is data from another PRC2 inhibitor called tazemetastat or TAZVERIK, which is an approved compound approved for the treatment of advanced synovial sarcoma and lymphoma. It inhibits the PRC2 complex at the catalytic sub-unit as opposed to pociredir, which inhibits at a regulatory or guide sub-unit. But they both end up net effect of inhibiting the methylation activity of the PRC2 complex.
And the findings in tazemetastat were interesting in that they had observed malignancies in their preclinical toxicology program. And then in their clinical program, particularly in their pivotal clinical program, which was conducted open label in patients with advanced malignancies, they saw a 0.7% rate of secondary malignancies in those patients. If you look at the patients, obviously all of them had been pre-treated with either chemotherapy or radiotherapy, and sometimes both for their initial underlying diagnosis. And by virtue of that, were predisposed to secondary malignancies anyway. And in the absence of a control group, it's hard to understand fully is that really placebo or not. I think FDA took the conservative position that they were attributing that to drug. But I think it's a very, not I think, it is a very different patient population, and they clearly have risk factors.
So anyway, those were the reasons for the initiation of the hold.
As Alex mentioned, you guys were able to get the clinical hold lifted, I mean, really in record time, like six months. But there were some changes. So maybe you can just kind of walk us through those that have been applied to the patients that you're enrolling in PIONEER?
Yeah, so I'll start, and Iain, please jump in. So yeah, so we are off clinical hold. You are right, we were able to get off clinical hold in about six months to the day, primarily because there was not any additional clinical or preclinical data that the FDA was requiring to get off clinical hold. They were really asking us, again, the fact that this was a phase I-B study, they were essentially sort of asking us to more narrowly define the patient population to a more severe patient population. And there's really two components to that. One is the number of VOCs that the patient has experienced prior to enrolling into this study. So it's either four VOCs over a 12-month period of time or two VOCs over a six-month period of time.
But there could also be other measures of disease severity, such as if the patient has chronic kidney disease or pulmonary arterial hypertension, that will automatically make them included in the study, regardless of the number of VOCs that they had during the prior six or 12 months. So that's sort of one aspect of the restrictions that were put in place for this phase I-B study.
More severe patients.
Just simply a more severe patient population at this stage. The other one was they essentially were restricting patients who are currently on HU from being enrolled into this study. So it essentially had to be a de novo patient, i.e., was not currently on hydroxyurea or had previously tried and failed on hydroxyurea. I think the other thing that they had also requested is that the patient either had tried or failed on one of the more advanced therapies or not had access to them. That becomes less of an issue now, now that OXBRYTA is withdrawn from the market. So our estimates are that there's anywhere from 7.5%-10% of the patients specifically in the U.S. that meet this more restrictive inclusion-exclusion criteria, and so the goal now, obviously, is to all of our efforts and focus is getting this study up and running, getting patients enrolled.
We're pleased with the enrollment that we're seeing, getting 10 patients in the 12 mg, 10 patients in the 20 mg, seeing what that data looks like at the end of three months, and then going back to the agency in terms of what that new inclusion-exclusion criteria might look like for future studies.
Absolutely. So since you get to the point, and again, excited for data next year, what do you see as the regulatory path forward for pociredir? Obviously, it's going to be data dependent, and what is the opportunity overseas? You started to talk about how much larger it is and how patient access is negligible if even overseas. I mean, just as a drug, a one-pill drug, that could be.
Yeah, I mean, if you imagine the number of patients that are eligible for or that are accepting the cell and gene therapies in the U.S. representing 1% or 2% of all patients, you can imagine that is a 0% in the developing world, and there's 4.4 million patients around the world that have sickle cell disease.
Although this study, the first patient was from Saudi Arabia, so it wasn't even from America.
That's right. Yeah, but when you think about the number of that 4.4 million that are in sub-Saharan Africa, very, very different, so from a regulatory standpoint, there's really sort of two different paths that we are taking, two very separate and distinct paths. The first is continuing to engage with the hematology division of the agency, enrolling this study, getting that data in those patients, and then having that discussion both with the FDA as well as the EMA in Europe, for example, to really not only share with them the data, but also to sort of plan with what that next study looks like, and ideally, our goal would be to not only lessen the severity of the patient population for the next study, but also to increase the duration, so that's sort of one strand of activity that we're having.
The other strand of activity that we're having is with the group within the agency that is sort of cross-division, so not just within the hematology division, but a group that looks at the use of surrogate endpoints in these rare diseases where there continues to be high rates of morbidity and mortality. So the other strand of work that we're doing, at least internally right now, and then we'll be deciding in 2025 when best to approach the agency about this, but it would be essentially sort of communicating with the agency in this cross-division group within the agency that looks at the use of surrogate endpoints, in this case, fetal hemoglobin as the potential for an accelerated approval. So the agency obviously did that with OXBRYTA. So they approved OXBRYTA on total hemoglobin at the end of six months. They saw 1 gram per deciliter.
If you compare the abundance of evidence out there in the marketplace in terms of increasing total hemoglobin and the benefit that that has on morbidity and mortality compared to increasing levels of fetal hemoglobin, it's very difficult to make those comparisons because there's such a strong abundance of evidence out there, as Iain mentioned. Just the difference of 8% of fetal hemoglobin has a dramatic impact on survival, and that was shown in the early hydroxyurea study. Our plan is to really kind of formulate that strategy on why we would recommend potentially approaching the agency and having the discussion with them on using fetal hemoglobin as a surrogate endpoint for a potential accelerated approval.
Do you feel like maybe OXBRYTA muddied the waters a little bit with the agency? Is that a risk?
It's hard to say. I would say that the bare thesis is that, boy, the FDA approved OXBRYTA on a surrogate endpoint, total hemoglobin, and therefore they don't want to sort of run that risk again, and therefore they're going to be much more conservative. But the alternative, the bull case, is that this is still a patient population that has 30+ year reduction in mortality compared to all of us. And I think.
It's a different biomarker, like you said, that has a lot of validity.
Exactly.
Just got approved essentially with the gene editing therapy.
Correct.
Are there other hemoglobinopathies that could be used or could be addressed with this mechanism?
Yeah, absolutely. And I think the one that gets the most focus is probably the beta-thalassemia group, and we are certainly well aware of that. Our approach at the moment is to navigate through the current trial, the PIONEER trial in sickle cell disease, and then to start to incorporate other hemoglobinopathies like thalassemia. So that'll be a staged approach into that particular indication.
One thing on the third quarter, call, I was so pleased to hear that you guys are reinitiating discovery activities. I remember when I first started working with the company, FulcrumSeek was really how you guys were learning about transcription factors and different things like that that could be a drug. What can you tell us about these early efforts?
Yeah, absolutely. I mean, pretty oddly incoming, but pretty excited about the deal that we did with CAMP4 about a year and a half ago where we brought in a host of compounds looking at potentially using those in certain inherited aplastic anemias, such as Diamond-Blackfan anemia, Shwachman-Diamond syndrome. So there's a number of these inherited aplastic anemias for which each one probably has 3,000-4,000 people in the U.S. So clumping those together, it could be potentially a real sort of interesting market opportunity. But maybe just talk a little bit about some of the work that we're doing there.
Yeah, more broadly, benign hematology is a big focus and continues to be so in the discovery group. The whole aplastic anemia side, [building] off the CAMP4 acquisition, is really our most advanced discovery program at the moment. But we also have a continued interest in fetal hemoglobin induction more broadly, and so we have efforts ongoing there, and then we also have additional efforts in the rare disease space that are not specifically focused on hematology, so there's a broad range of activities occurring in the discovery pipeline.
Great. And you guys still have a very healthy cash position, I think over $250 million at the end of the third quarter. How long does this fund the company? And what's it really enabled you to accomplish?
Yeah, it's a great question. So you're right. Third quarter, we had $257 million. We've guided that this year will end the year with $240 million. Our burn, which is a very efficient burn in 2025, is somewhere between $55 million and $65 million. So that gives us a cash runway into at least 2027 and possibly beyond. And what that enables us to do, that assumes success on pociredir, so it allows us to advance that to a registrational enabling study, as well as continuing to build on all the great work we're doing on the discovery side and bringing those programs into the clinic as well.
It's going to be an exciting year.
It certainly will.
Looking forward to data. Always here to help.
That's great. Yeah.
Thanks for being with us.
Yeah, thanks, Ted. Really appreciate your time.
Thanks. See you.
Thanks. Thanks so much.