To our chat with Fulcrum Therapeutics. I'm Joe Schwartz from the equity research team at Leerink Partners. It's my pleasure to host Alex Sapir, CEO, and Iain Fraser, SVP of Clinical Development. Thanks so much for joining us.
Thanks for having us. Thanks for everybody for joining us in the audience.
Now that it's been a few weeks since you announced the full PIONEER data, what are the key takeaways from the study, and what feedback have you heard from the KOL and patient community?
Yeah, no, it's a great question, Joe. It seems like two weeks was years away. Yeah, the feedback from the physician community has been overwhelmingly positive. I think what they've been most impressed with, there's really two factors. The first is the robust and rapid induction that we saw in fetal hemoglobin, given what we know in terms of this relationship, that as you increase total hemoglobin, you see a reduction in VOCs. We saw patients coming in to the study at 7.1%, and by the end of the study, they got up to 19.2%, sorry, 19.3%, or a delta of 12.2%. I think the second thing that the physicians were also really excited about was just the totality of the data.
We saw all of the key markers of hemolysis, LDH, bilirubin, retics, RDW. They were all trending in the right direction, going down, showing that there was less hemolysis. Because of that, we also saw an increase in total hemoglobin, which should help patients' fatigue. The drug in this 12-week study appeared to be very well tolerated. We saw a really interesting, encouraging, albeit early trend in VOC reduction. I'll leave you with this thought. There were some physicians that, when we were first recruiting for the PIONEER study said, "You know, it's still early and I'm gonna sit on the sidelines.
Why don't you come back to me when you've got more data to share?" at the ASH conference, and then more recently, I've actually had many physicians proactively reach out to me and said, "Please keep me in mind with your next, for your next study. This is really impressive data, and we really wanna be a part of it.
That's fantastic. In PIONEER, you only saw six VOCs versus 16 which were expected over the 12 weeks. How should we think about that signal translating into a longer 52-week registrational study?
Yeah. Yeah. I think Iain and I are gonna tag team on this one. You wanna take that one?
Yeah. Yeah, absolutely. Yeah, and importantly, there were seven of the 12 patients who did not have a VOC during that treatment period. I think we're particularly encouraged because it's early on in the trajectory, so during the 12 weeks of the treatment period. The HbF is continually increasing during that period, so they're not at steady-state maximum effect, which they would need to get to before you could evaluate the VOCs entirely. Very encouraging to see that early signal in a short duration. That certainly encourages us for a longer duration where we'd expect the patients to reach maximal HbF effect and be at that level for a longer period to assess it.
We also know given the magnitude of HbF that we're seeing induced here in these patients, that puts them in a range where we would certainly expect to see lower rates of VOC. We're encouraged on both of those counts.
Yeah. Great. Do you expect the reduction in VOCs to remain proportional to the HbF increases over time, particularly at higher HbF levels around?
Yeah. You know, again, I think you need to get to that steady state level before you can really assess the full magnitude of the HbF induction. It's not just the hemolysis of the red blood cells. There's an endothelial cell component to it as well, an inflammatory component as well. I think, you know, the system needs to reset at the new steady state before you see that maximum re-reduction. As the HbF increases, absolutely, you start to see a decrease in the VOCs. It plateaus out in the 20s. In the mid-20s you don't really get incremental reduction in VOCs because it's pretty close to maximum. The curve is pretty flat from the mid-teens up to that 25% range, but there is some additional increment to be had there.
Okay. While almost 60% of patients got HbF levels of at least 20%, how are you thinking about the roughly 40% who didn't reach that mark?
Yeah. I think that, I mean, the good news is that, every patient saw an increase. On average, of the 12 patients that we evaluated, they all saw at least a 6.5% absolute increase in their fetal hemoglobin or greater. As you mentioned, seven out of the 12 got to above 20%. Even if you look at those patients that started at very, very low levels of HbF, I remember, I think it was patient 9, I believe, they started at 1.5%. By the end of the study, they got to 9%.
Even though they didn't hit that 20% that Iain talked about, you know, that delta of seven for that individual patient is going to be very clinically meaningful, and that could take a patient with, say, maybe four VOCs down to two VOCs. Two times two less VOCs, meaning-
Two less times of being admitted to the hospital, being admitted to the intensive care unit, that's gonna be clinically meaningful for those patients. For us, as we think about our next study, some people have asked us, "Well, you know, why don't you just exclude patients that are at that low level, right? Just take patients that are at 10% or greater." That would certainly help, I think, improve the likelihood of more patients reaching 20%. I actually think that would deprive some of those more severe patients that have very low levels of HbF at, say, 1%, 2%, 3% of seeing that incremental benefit that clearly is going to be clinically meaningful for that patient.
Yep. Makes sense. Are there any post hoc analyses that you're working on to understand if there are any similarities between people who respond more or less?
Yeah. We had that observation, particularly in the 12-milligram cohort. Again, every patient in that cohort, there were 16 evaluable patients. Everyone responded by increasing their HbF. There were a couple of patients who did not have very robust responses. Some of them were related to having received multiple blood transfusions, and that just falsely depresses the HbF because it dilutes it out with normal hemoglobin. There were a number of the other patients who tended to have lower baselines and lower responses. When we dug into that a little more, most of those patients were from the single site in South Africa, that we had open at that time. It turns out that those patients came not from South Africa, but they came from Democratic Republic of Congo further north.
We know that there's a very high frequency of a sickle cell haplotype that's called CAR, Central African Republic, sometimes called Bantu haplotype, that's associated with low baseline HbF severe disease and also interestingly, a lower responsiveness to hydroxyurea. We don't yet have the DNA sequencing on those patients to confirm that, but certainly epidemiologically, that's an association, and we're looking to confirm that. We did not see that magnitude of effect at the 20-mg dose, in part because we only had 1 patient from the South African site. We enrolled some additional patients from Nigeria. Again, based on the epidemiology of haplotypes in Nigeria, we expect them to be much more heterogeneous, much more mixed, more similar to the US patient population than to the DRC population. That does not seem to be a feature there.
Bearing that manifestation in mind, one of the things as we move into a pivotal study that we're conscious of is that geography may play a role here, and that potentially stratifying based on geography might be an important component just to ensure that we don't get an imbalance of, you know, less responsive patients potentially in the treatment group or more responsive patients in the placebo group.
Yeah, that makes sense. Patient 10 had their HbF go from 34% at one point to 29%. Is that just due to assay variability, or are there any reasons that you can point to that?
Yeah. We noticed that patient particularly and have dug into that and looked at that patient. It was anomalous because in the study to date across all the lower dose cohorts, we've not seen an instance where on study the HbF is higher and then goes down. We've seen a few patients where it tends to plateau maybe a little earlier than the 12 weeks, but we haven't seen that phenomenon of going down. That was a little surprising to us. In reviewing all the labs, we haven't identified any particular reason for that. I think we're left with this is part of the variability of the assay.
I do wanna point out that particular patient started out with a baseline of 8%, and it went up to 34%, which was amazing, but ended up at 29%, which is pretty darn good irrespective. We're not overly concerned about that, and I think it was just that one anomalous reading that seemed a little odd relative to the rest of the study.
Right. Okay. What gives you confidence in the hematologic safety over time?
Yeah. Take that in two buckets. The first is obviously on the red cell side. What we're seeing as we treat these patients with Pociredir is that the reticulocytes come down and they come down very nicely. They're not quite at the normal level at the end of 12 weeks, but they're approaching that. That is an expected therapeutic response. There's less stress on the bone marrow, the bone marrow is churning out fewer reticulocytes, and you see that in the gene therapies as well, where the retics come down. Most importantly, in the context of the retics coming down, the total hemoglobin is going up. If the retics coming down were a manifestation of bone marrow suppression, you wouldn't expect the total hemoglobin to come up.
What I think you're seeing is the less stress on the bone marrow, but as those cells that are coming out have more fetal hemoglobin in them, they're less prone to hemolyze, they don't get destroyed as quickly, their half-life is longer, they survive in the circulation longer, and so the total hemoglobin goes up. That's consistent with the HbF hypothesis and very encouraging to see the total hemoglobin going up as the F goes up. With respect to the other lineages, we've not seen adverse events of cytopenias, with the one exception that we disclosed in the 20 mg cohort of a patient who developed cytopenias that was in the context of an upper respiratory tract infection. They were positive for parvovirus B19, which is known to suppress the bone marrow.
Their counts came back when we restarted Pociredir, so we held it for a time. Not sure whether the effects we were seeing were related to the drug or perhaps this intercurrent infection, when they stabilized, we restarted Pociredir, those counts came back up. With the exception of the reticulocytes, which didn't go back to baseline, but as I mentioned earlier, that's part of the therapeutic response, the retics go down, so we wouldn't have expected that. That was the one sort of, again, outlier there. Otherwise, very reassuring from an AE perspective.
Yep. Okay, great. Looking forward, is the streamlined regulatory package that you're submitting to the FDA specifically a blended trial design where you might propose a accelerated approval possibility using HbF as a surrogate endpoint and then a longer term look at VOCs for full approval?
Yeah, great question. Very important end of phase meeting coming up with the agency sometime very soon, and we should have guidance on the outcome of that discussion with the agency that we'll be able to share with everybody in the second quarter of this year. The approach that we're going to take for that meeting is we believe that in this more severe patient population, we have demonstrated a robust clinical benefit, and therefore we are going to propose to the agency to move forward with a registrational study as our next study that if successful, and if the FDA agrees, we would kick that off in the second half of this year. That registrational study is probably somewhere between 200-300 patient study.
We would be in that study, we would be looking at VOCs at the one-year mark, very similar to the way the other companies have done it. Given this very strong and important relationship between fetal hemoglobin induction and reduction in VOCs, what we're also going to be proposing to the agency is within that same study, look at a smaller subset of patients, not the full 200-300 patients, but call it half of that at the six-month mark looking at HbF. If that is deemed successful at that six-month time point, at that point, we would then be requesting an accelerated approval. That's sort of our plan. One study powered on VOCs with an interim look at HbF at the six-month mark in roughly half of those patients.
Okay. How much have you looked at the powering so far for such a study giving Mitapivat showed, you know, a miss on the-
Yes
statistics for VOC reduction?
Yeah. We have spent, as you can imagine, a lot of time looking at powering assumptions and all the different variables that go into that. Our resident sort of statistician, I'll have him answer that question.
Being promoted to statistician now. Yeah, it's obviously been a key focus, as we've looked at all the studies that have been conducted recently with a VOC endpoint and taken away a lot of the learnings there. One of the learnings is, powering on an expectation of VOC rate in the placebo group, and in general, what we've seen in previous studies is that they've assumed a higher rate of VOCs going into the study compared to the placebo VOC rate that you can observe at the end of the study, so overly optimistic on what the baseline is.
We're being very cautious about factoring that in, and I think that's one of the potential advantages of going into a more severely impacted patient population, is that those baseline VOC rates tend to be higher, and so that helps on the powering assumption. That's the one aspect. Second aspect is around the dispersion coefficient of those VOCs, in other words, how much variability in that VOC rate there is in that population. You know, are they all clustered towards the low end or are they more evenly distributed across the entire range? We've taken a very conservative approach there, so that we don't underestimate the dispersion characteristics of that. Then the other, probably the most sensitive marker on powering is the effect size.
You know, if your drug doesn't reduce VOCs, it doesn't matter how well you power the study. It's probably not gonna work at the end of the day. We're using really the HbF induction levels that we're seeing as a surrogate for projection of what sort of magnitude of VOC reduction we might see. That's gone into the calculus as well, and then also you have to factor in the dropout rate, and being conservative at that end, in the 30% dropout range, makes the study a little bigger, but it also provides a little extra cushion because those dropouts, particularly if they're early in the study, can really hurt you on the VOC endpoint.
To what extent do you expect to be able to harmonize guidance with the EMA? Have you had pretty consistent feedback throughout development from regulatory agencies around the world?
Yeah. Great question. We have guided that sometime around the middle of the year, we will be engaging with the European Medicines Agency.
This will be our first time engaging with EMA, so we don't know the degree to which they're thinking some type of harmonious type of clinical development program. I will say that in my own experience, I think that both EMA and FDA have a strong appreciation for rare disease and some of the challenges of enrolling studies in rare disease, and because of that appreciation, I think the more harmonization that the EMA and the FDA have in terms of what that next study looks like. I think they have a strong appreciation for the fact that that has the potential to get the drug that may be beneficial to patients quicker to the market, and especially in sickle cell where there is such a high unmet need.
My guess is I don't think that we'll see EMA have a set of parameters in terms of what the next study looks like and the FDA have a set of parameters in terms of what the next study looks like, and those are dramatically different from one another for the reasons that I mentioned.
Okay. I think I've heard you say that you think that the future label might not specify a minimum number of VOCs. You've had, you know, a restricted enrollment criteria.
Yep
To date. How do you anticipate flexibility might impact your trial design? Do you think you'll probably have a similar design in the phase III as you had in PIONEER?
Yeah. Great question. I mentioned a little bit earlier that the plan is to go forward with a registrational study in a more severe patient population. I think building on Iain's last comments, targeting a more severe patient population in terms of a higher number of VAs-VOCs, I think in essence you're sort of enriching your patient population, and it absolutely improves the powering. It also improves the probability of clinical success as well. Right now, the patients that represent our current inclusion/exclusion criteria is roughly around 20% of the overall population, and here's why I'm not as concerned about once we do get approval, only being indicated and being able to promote against that 20%.
You know, if you look at the hydroxyurea, the Casgevy, and the Lyfgenia phase III studies, they all had different VOC criteria. HU was patient had to have three VOCs in the preceding 12 months. Casgevy had, the patient had to have two VOCs during the preceding 12 months, but that had to happen across two consecutive years. Lyfgenia was even different, which is you had to have four VOCs over a 24-month period of time. They all had different entry criteria in terms of the number of VOCs, and yet that is not in any way reflected in their indication statements.
Now, what their indication statements do say is for the treatment of patients with severe sickle cell disease or for the treatment of patients with sickle cell disease with recurrent VOEs, and so we don't know what our our label is going to look like. In a scenario where the FDA takes a similar approach to the approach that they've taken for other approved therapies, I believe that a label that looked similar to some of the other drugs would allow us to promote to a broader patient population than just the 20% that we're currently targeting with our current enrollment criteria with PIONEER.
Do you see any impact from the recent withdrawal of Ipsen's tazemetostat?
Yeah. It's a good question. I will tell you that has probably been, through our one-on-ones today, question number one on everybody's mind and just to level set for everybody. Yesterday, Ipsen announced that they were stopping development of t azemetostat or Tazverik, which is a PRC2 inhibitor, in a SYMPHONY-1 trial for the treatment of follicular lymphoma, and they will also be stopping the promotion of that drug as well. In essence, they're voluntarily pulling it off the market. They are a PRC2 inhibitor. Pociredir's a PRC2 inhibitor, so the big question on everybody's mind is, what potential read-through does this have? I will leave you with two thoughts there.
The first thought is that, even though they are both PRC2 inhibitors, they both target a very different place on the PRC2 mechanism. Tazverik or t azemetostat targets EZH2. We target EED, and we think there's a very sort of clear distinction in those two targets. I think the other important point to make is that, this risk-benefit calculus is very, is very disease specific. I don't think you can make a broad generalization of a risk-benefit for Ipsen in follicular lymphoma is necessarily going to be the same risk-benefit, for sickle cell disease with PIONEER.
I think making this sort of blanket, well, if the risk-benefit was too great for t azemetostat , which is an EZH2 inhibitor, not an EED inhibitor, in a cancer indication unlike a sickle cell indication, I don't think you could make a broad generalization that that risk-benefit translates over to something like Pociredir, which is an EED inhibitor in a non-cancer indication such as sickle cell disease.
Right. There's a lot of need. I guess let's shift gears a little bit and I'm wondering how do you think about the logic of potential partnerships such as ex-U.S. at any point?
Yeah. We believe that the greatest return that we can generate for our shareholders is to get this drug approved as quickly as possible and to commercialize it ourselves, specifically in the U.S. We're a relatively small biotech company with a very rich cash reserve, but 50 people strong. One of the things that I think about every day, Joe, is how do we make sure that those 50 people are focused on the absolute most critical activities that we need to over both the short and the medium term? I think for us as a company to look to maybe commercialize this drug outside of the U.S., in particular, in Europe, I think would potentially be something that would be biting off more than a small company could chew.
lot of opportunity costs of doing that, a lot of spreading your effort across too many areas. I think potentially when we get to the right point where we wanna start talking about potential partnerships, I think more than likely you would see a potential partnership outside of the U.S., but with us commercializing it ourselves in the U.S. No different than the success that Global Blood Therapeutics had commercializing Oxbryta in the U.S. by themselves.
Right. Okay. With cash runway into 2029, you're funded through your first pivotal readout. Does your vision for the next two years or so focus almost exclusively on the sickle cell program?
It does. It kinda goes back to what I said before. We're a small company, and I tell the team, "You have to get up every day and think about what do we need to do to get us to that next value inflection point." I would say that for the next 18-24 months, it's ensuring that we can have the most successful end-of-phase meeting with the regulatory agency, and if that meeting is successful, kicking off that registrational study as quickly as possible in the second half of this year and getting that study enrolled as quickly as possible. That in and of itself, if we can just do those two things over the next couple years, the value that we'll be able to create is very significant.
I think more broadly, over the next five years out to 2030, we do have ambitions to become a world-class benign heme company, not just in sickle cell, although that's really where our expertise is, today. There's a number of opportunities that we're looking at, both from our own discovery efforts as well as potential in-licensing opportunities to become that world-class benign heme company over the next five years. At least in the short term, over the next couple of years, it is really focused squarely on preparing for the regulatory interactions and, most importantly, kicking off what we hope will be a registrational study in the second half of this year.
Great. Maybe just a few words on the status of the DBA program.
Yeah.
What's the timeline?
Yeah. As we disclosed at our last earnings call, we've made the decision to discontinue that particular program. Just a few comments on that. We were marching towards an IND there. As we had done with Pociredir, we set up a strict set of criteria for what we considered to be an appropriate target product profile for an agent to treat DBA and bone marrow failure-related syndromes. As we progressed through the IND-enabling studies and our discovery team put an enormous amount of effort into that, it became clear that we were not going to be able to meet that rigorous target product profile that we'd established for use, and so made the decision that we would refocus our energies on the sickle cell program and allocate the resources there.
That was the decision that was made earlier this year.
Okay. Great. Well, thanks so much for the update. Keep up the good work.
Yeah. Thank you so much. Thank you.