Fulcrum Therapeutics, Inc. Price & Performance (FULC)

With that, it's my pleasure to turn the call over to Alex. That's great. Thanks so much, Marvin.

Good morning, everyone, and thank you for joining us today. The latter part of 2024 and early twenty twenty five has been an exciting period for Fulcrum Fulcrum. With notable progress for our lead program, POCERIDER, currently in development for the treatment of sickle cell disease. With the team we have in place, a year end cash position of $241,000,000 and lastly, two data readouts over the next twelve months. 2025 is poised to be an important year for Fulcrum and more critically for patients with sickle cell disease and other benign hematological conditions. So let me get into some of the details and begin by giving an update on POCERIDR, our oral HBF inducer the treatment of sickle cell disease. As many of you know, sickle cell disease is a lifelong inherited blood disorder that severely impacts quality of life for approximately one hundred thousand people in The U. S. And four point four million people worldwide. Historically, standard treatment for sickle cell disease has involved blood transfusions, pain medications and hydroxyurea focusing primarily on symptom relief. And despite the approval of gene editing therapies and their ability to increase fetal hemoglobin levels to transformation to transformational levels for patients, there remains a significant unmet need for safe and accessible oral therapeutic options that are broadly protective of sickle cell symptomatology.

This unmet need is further underscored by the recent global withdrawal of OXprata. And it's the first in class oral small molecule HBF induced we believe Pocere Deer has the potential to address this high unmet need In our Phase 1b trial of pocere dheir, which we call the PIONEER trial, we have made good progress enrolling patients and activating sites. And I am pleased to report that we recently enrolled our tenth patient in the twelve milligram cohort with the potential to enroll additional patients currently in screening prior to the next cohort, the twenty milligram cohort, being open for enrollment. Based on the progress that we've made with enrollment, we remain committed to share data from the twelve milligram cohort in mid-twenty twenty five and the twenty milligram cohort by year end. Now just as a quick reminder, patients enrolled in Cohort three receiving twelve milligrams of POCERIDR once daily while patients in cohort four will receive twenty milligrams once daily. Each cohort has a dosing duration of three months followed by a one month follow-up visit by the patient. We believe that inducing fetal hemoglobin is the optimal strategy for treating sickle cell disease. Evidence for the benefits of fetal hemoglobin continues to grow as highlighted by the recent data presented at ASH last December showing that even modest increases in HBF correlate to reduced disease severity.

Specifically each 1% increase in HBF was shown to provide a four percent to 8% reduction in painful and at times debilitating basal occlusive crises or BOCs. Furthermore, once HBF levels reach into their mid-20s, patients experience a near abolition. Of VOCs.

Based on Pocere deere's mechanism of action and the data that we have previously disclosed, we believe that living with sickle cell.

Beyond PocereDARE, we continue to make progress in other rare benign hematological conditions. In particular, are currently conducting IND enabling studies for an oral compound we believe has the potential to treat inherited aplastic anemias such as Diamond Blackfan anemia or DBA for short Schwabman Diamond syndrome and Fanconi anemia and we plan to submit an IND for Diamond Blackfan Anemia in the fourth quarter of this year. With that, let me now turn it over to our Chief Financial Officer, Alan Musso to run through the financials. Alan, over to you. Thanks, Alex. I'll now go over our results for the fourth quarter and for the full year ended 12/31/2024. Beginning with results for the quarter. We had no collaboration revenues in the fourth quarter of twenty twenty four compared to $900,000 for the fourth quarter of twenty twenty three. The decrease was due to the completion of our research services under our MyoKardia collaboration agreement during the fourth quarter of twenty twenty three.

Our research and development expenses were $11,700,000 for the fourth quarter of twenty twenty four compared to $19,000,000 for the fourth quarter of twenty twenty three. The decrease of $7,300,000 dollars was primarily due to decreased costs associated with the discontinuation of our losmapamod program and global development cost sharing reimbursements. Partially offset by increased costs related to the advancement of the Phase 1b PIONEER trial.

General and administrative expenses were $7,700,000 for the fourth fourth quarter of twenty twenty four compared to $9,900,000 for the fourth quarter of twenty twenty The decrease of $2,200,000 was primarily due to decreased employee compensation costs, resulting from the workforce reduction implemented in the third quarter of twenty twenty Our net loss was $16,600,000 for the fourth quarter of twenty twenty four compared to a net loss of 24,800,000.0 for the fourth quarter of twenty twenty three. [indiscernible] I'll now review the results for the full year ended 12/31/2024. Collaboration revenue was $80,000,000 for the year ended December 31, 2024, compared to 2,800,000.0 for the same period in 2023. The increase of $77,200,000 was primarily due to recognition of the $80,000,000 upfront license payment received from Sanofi during 2024. The research and development expenses were $63,400,000 for the year ended 12/31/2024, compared to $71,800,000 for the same period in 2023. The decrease of $8,400,000 was primarily due to global development cost sharing reimbursements under the collaboration with Sanofi partially offset by increased costs related to the advancement of the Phase 1b PIONEER trial. General and administrative expenses were $36,400,000 for the ended 12/31/2024, compared to $41,700,000 for the same period in 2023.

A decrease of 5,300,000.0 was primarily due to decreased employee compensation costs as a result of the workforce reduction implemented in the third quarter of twenty twenty four. Our restructuring expenses were $2,100,000 for the year ended 12/31/2024, compared to no restructuring expenses. During the same period of 2023 The increase was due to the workforce reduction implemented in the third quarter of twenty twenty four primarily related to severance costs. And our net loss was $9,700,000 for the year ended December 31, 2024, as compared to $97,300,000 for the same period in 2023.

And now turning to the balance sheet.

We ended 2024 with cash, cash equivalents and marketable securities of $241,000,000 compared to 236,200,000.0 as of 12/31/2023.

The increase in our cash position was due to the $80,000,000 upfront payment we received from Sanofi in the second quarter of twenty twenty four. Partially offset by the cash used to fund our operating activities in '20 And finally, turning to cash guidance. Based on our current operating plans, continue to expect that our existing cash cash equivalents and marketable securities will be sufficient to fund our operating requirements into at least 2027. And with that, let me turn the call back over to Alex. That's great. Thanks so much, Alan. And so with that overview of the business and the financial that Alan just went through, Marvin, let's go ahead and open it up for questions.

Thank you. At this time, we'll conduct the question and answer session. And our first question comes from the line of Kristen Kliska of Cantor Fitzgerald. Your line is now open. Hi, this is Rick Miller on for Kristen. Thanks for taking our questions. We've just got two for you today. Can you give us any color on when you would look to meet with the FDA as it relates to the twelve milligram and twenty milligram cohort readouts? And also, what do you think the bar is on now that there have been changes in the sickle cell space? Thanks.

Yes. I think to answer that question, Rick, thanks for asking It's a good question. I think to answer that, let me I'll turn it over to Ian and then if I've got any sort of additional comments to make, I can add those after Ian, over to you. Yes. Thanks, Alex. Thanks, Rick, for the question. So what we've said in the past is that we aim to complete the twelve milligram and the twenty milligram cohorts before going back to FDA to review the next steps in the program However, we've also said that depending on the data emerging from the study we could potentially go back to the agency earlier with the data from the twelve milligram cohort itself. So all dependent on the data emerging from that cohort and we will review it and make that decision at the time.

To your second question, Tabar for Which relates to the extent of fetal hemoglobin induction I think there have been a number of movements in the space that have really reinforced the importance fetal hemoglobin in the overall treatment of sickle cell disease.

Both from the gene therapy side where increases in fetal hemoglobin that is extended up into the low 40% range have shown to be clearly transformational for those patients in terms of their reductions of acute symptoms. The overall data epidemiologic, pharmacologic and genetics suggest that there's clearly benefit to be gained from increases of fetal hemoglobin that are even lower than that. We know as Alex mentioned in his remarks at the beginning of of this meeting were published by Novo at at ASH just this last December, which was a review of previously conducted studies in the sickle cell space indicated that one percentage point increase in fetal hemoglobin was associated with a 4% to 8% reduction in acute VOCs. So even at that relatively low increase in fetal hemoglobin, there is benefit to be had. If we look at what's being approved based on VOCs, L glutamine, was approved by FDA with a 25% reduction in BOC. So that at least was one benchmark for what was considered to be clinically meaningful in that space. So I think that's the one piece of it. And then the other piece is some work that we've done ourselves and this is in our corporate deck analysis of real world data from PIPNIC Health indicating that as you increase fetal hemoglobins from very low levels, up to around the mid-twenty percent range, you get an an incremental reduction in the likelihood that you'll experience a BOC during the year and at that mid 20% range the curve flattens out and the probability of having a VOC in the following year is close to zero.

And so putting those two together, small increases can be clinically meaningful and beneficial once you get to the mid-twenty percent range. Transformational for the patients.

And then Rick, this is Alex. The only other thing I would add related to your first question in terms of engagement with the agency. And we've stated this in the past as well as a separate work as a separate work stream we do plan to engage with the agency on the use of fetal hemoglobin as a surrogate endpoint potentially for our next study that we would conduct with posterior dystrophy. So those discussions are ongoing. But I think as Ian said, any increase in fetal hemoglobin shows [indiscernible] reduction in VOCs and then once you get to that mid-twenty 5% that's when you see a near evolution of VOCs. So I think there's a tremendous amount of data on the use of HBF and its impact on clinical manifestations of the disease. And so we will be engaging with the agents on the possibility of using HBF as a surrogate endpoint for the next study that we plan to conduct with POCERIDERE.

That's great. Thank you for the color.

Yes.

Thanks so much.

Our next question comes from the line of Joe Schwartz of Living Partners Your line is now open.

Great. Thanks very much. I was wondering if you can give us any insight into the types of patients who have been enrolling in PIONEER today given the detailed rubric required to identify those who are eligible to enroll involves a number of criteria. I'm just wondering if any particular patterns are presenting themselves especially now that the withdrawal of EXPARIDA might be influencing things And then I have a follow-up. Thanks.

Yes. Thanks, Joe. It's a good question. Appreciate you asking. I'll start and then I'll I'll turn it over to Ian for any additional color that I missed. So the 10 patients that we have enrolled to date come from both South Africa and The U. S. As you articulated in your question, these patients do tend to be on the more severe side. So it would not be unexpected to see their their baseline fetal hemoglobin lower than what we showed in the first 15 patients that were enrolled in this study, but we have yet to share details any of the details around baseline fetal hemoglobin. And I think as we previously have said, our plan is to release the full dataset once that does become available. And again, we do remain on track to share that data in the twelve milligram cohort by by midyear. [indiscernible] Anything else you would add to that Ian?

We've spoken about the specific inclusion and exclusion criteria for for the new part of the study emerging from the clinical hold and I feel the patients are conforming to those new inclusion exclusion criteria. So don't think there's anything surprising different or any unusual patterns that are emerging from that to date. It's pretty much in line with what we expected. Based on those inclusion and exclusion criteria We do, obviously, have benefit of patients now not being able to access OXELOt or OXPRIDA Those patients have to wash out of that therapy And so that process is sort of just coming to fruition now. Not everybody stopped immediately on the day it was withdrawn. But those patients are obviously lacking in other options. And they do have the option of enrolling in our study. Maybe, Jesse, only other thing I I would add is the high level of of adherence to study drug that we are seeing. So we're using a pretty innovative AI tool from this company called AI Cure that really sort of monitors patient taking the drug on a on a daily basis. And we're seeing adherence rates across these 10 patients that have enrolled.

We don't have a lot of data on the 10 patients. They were only recently enrolled. We're seeing adherence to study drug rates in the north of ninety percent. So that's also been really pleasing to see.

Okay, great. Thanks. That was going to be my second question. So I appreciate that color. But maybe I can just ask, whether there's a particular hurdle that the DSMB needs pacirid area clear before it can advance to the twenty milligram cohort. Can you talk about how that process of evaluation will go with the DSMB.

Yes, sure. I'll sort of provide a couple of the facts and I'll turn it over to Ian to get into more specifics in terms of exactly what DMC, the data monitoring committee is looking for. So So just to remind everybody, once the eighth patient has completed their thirty days of of dosing, that is when we can call the DMC together to review to review the data and I'll have Ian just touch on that in just a minute. So that that meeting with the DMC is in the process of being scheduled. As you can imagine, these are busy thought leaders. So in addition to making sure that that eight patient has completed the thirty days of dosing, it's also just logistically making sure that the schedules of all of these busy people are aligning. But that scheduling of that DMC meeting to review that data is is in the process of being scheduled. Do you want to maybe talk a little bit about what the DMC is actually looking for?

Sure. Happy to do that. And maybe just to add that there always was right from the beginning of the study, which is a first in patient dose escalation, there always was a pause between sequential cohorts with a review of the data in order to allow the subsequent cohort to proceed. And that review always primarily focused on safety and tolerability. The DMC now will convene to review the twelfth milligram cohort with respect to advancing to the twenty milligram cohort and their focus is again primarily around safety and tolerability, the acute safety and tolerability of the compound they will have access to and will review HBF data and any other associated eptological data with the primary motivator or the primary decision around progression twenty milligrams will be based on on the safety and tolerability observed.

Thanks for all the color. Yes. Thanks, Joe.

Our next question comes from the line of Matthew Biegler of Oppenheimer. Your line is now open.

Hey, good morning guys. Thanks for the update.

Maybe just a little bit more granularity on the type of data that we're going to be getting for midyear and then year end is it? You think it will be mature enough to have a readout on any early VSC [indiscernible] midyear, I mean, I'd imagine you're probably seeing a pretty high baseline rate of VOC given kind of the sicker new patient population you're enrolling. Maybe just like any details around kind of what we should expect in terms of the types of data would be super helpful. Thanks.

Yes, great question Matt. I appreciate you asking it. And I'll start and then maybe turn it over to Ian for any additional color. So I think if you look at the data that we shared in the first 15 patients where we showed HbF levels at baseline and then at the end of the study. I think we will certainly be sharing that We'll also be sharing other biomarkers such as reticulocyte counts, red cell, cell distribution with. I believe that VOCs is something that we are obviously something that we are tracking, but I think given the fact that this is only a three month only a three month study where the patients are on drug for a period of of three months. I think it would be sort of unlikely to see a reduction in VOCs during that relatively short period of time. But maybe let me kick it over to Ian to see what additional color he can add Yes, we'll certainly provide that data. The study obviously is not focused on that as an efficacy readout. For the reasons that Alex just mentioned, but we are collecting the data and what I think we will have at a higher level than we did have with the previous cohorts is what the frequency of VOCs of these patients coming into the study was.

Originally, when the study was an all comer study, there was no requirement for severity until those VOC frequencies were not captured in the database in the same way as they are being now because of the inclusion exclusion criteria. So we will have a little more granularity around the baseline BOCs of these patients and then we'll report out the BOCs that occur on study as well. But short duration of the study and so on. Yes. And then maybe Matt, just the other thing add which I failed to which is probably important given the fact that this is a Phase 1b safety study is obviously we'll be sharing all of the important safety data as well that generates Fulcrum these from these 20 or some odd patients that we'll have across these two cohorts.

Awesome. Looking forward to it.

Thanks. Thanks so much, Matt. Thank you. One moment for our next question. Our next question comes from the line of Tazeen Ahmad of Bank of America Securities. Your line is now open.

Hi, this is Jeremy Miller on for Dazeen. Thanks for taking our question. Maybe a quick question on the FSHD readout that's expected in March. Wondering what the key takeaways you guys are thinking will be from the presentation. And if there's any potential interest in exploring FSHD with another follow on program just given your past experiences?

Thanks.

Yes, Jeremiah, it's a really good question. I appreciate you asking. I'll start and then I'll turn it over to Ian to provide additional color. So as we said when we shared the data to the top line, late last year. We are committed to make sure that we present this at the MDA Conference, which is now scheduled for March 19 type of lead. And then we will obviously be publishing it sometime sometime around midyear. I think what's interesting about this data set is, the drug performed as we would have expected and it performed very consistently with what we saw in the in the Phase two study. The challenge was is that during that fifty two weeks that the placebo has performed better than we had expected. So on a placebo adjusted basis, there was no change. Obviously, the prevailing hypothesis is could it be during that year that the mind overtook the disease recognizing that while this is a relentlessly progressing disease, it is slow to progress. And so so the prevailing hypothesis is could you do a longer term study two years, for example, where the mine does not have the ability to continue to overtake the disease during that two year period, but the disease overtakes the mind.

And I think we feel that that is not the most appropriate way to deploy our capital right now. So we do not have any plans to continue with Los Mapima. But it is quite possible that one of the other players in the FSHD field may have an interest in looking at that data when it finally gets presented and published and possibly sort of taking it taking it and conducting that longer term study.

But for us as a company, we feel the most appropriate way to deploy our precious and scarce capital is really focused on the exciting things that we have going on in benign hematology, in particular sickle cell and then some of these other inherited aplastic anemia that I spoke about. Ian, anything you want to add?

Just to be specifically MDA oral presentation, which Alex alluded to, is focused on the primary endpoint the key secondary endpoints and the safety So that those will be the highlights from that presentation. And then we're also preparing a more detailed manuscript that will include those endpoints but also a broader array of the secondary endpoints as well. So that's the manuscript that we intend to publish later on. We also have additional work going on to ensure that the work that we did around the regional workspace, the validation of that and so on the that too. Will be made public Great. Thanks for that color. And then maybe a quick question for Alan. Just curious on how we should be thinking about operating expenses in 2025 relative to 2024?

Should we expect to see some additional restructuring fees in 2025 or has that largely been completed? Yes. Good question. The restructuring activities are completed, but we do now have a smaller organization and we've guided that we anticipate our cash burn in 2025 to be between I'm sorry, dollars 55,000,000 and 65,000,000. So at midpoint of that, it's about 60,000,000. So per rough estimate, that's what we're thinking. Great. Thanks. Yes. Thanks, Jeremiah, for the question.

Thank you. One moment for our next question.

Our next question comes from the line of Edward Tenth of Piper Sandler. Your line is now open.

Great. Thank you very much and congrats on the progress Two quick questions. Just firstly, when it comes to The enrollment has That enrollment criteria. And then just secondly, when it comes to sort of the safety assessment, that the DSMB is going to be doing? Are there any special things we should be aware of beyond the standard that FDA is requiring? Thank you. Yes, two really good questions, Ted. Appreciate you asking them. I think I think you answered those and I'll turn those over to Ian. Yes, absolutely. And And Ted, thanks for the question. The issue around the HU is actually probably simpler now for the study than prior to the withdrawal of OX Brader, and simply because the language of the protocol specified prior experience with HU of the three at the time available therapies, which were Oxbrida, crizinlizumab and L glutamine know that both prisendilizumab and L glutamine have not had very wide uptake In the patient [indiscernible] being used fairly widely, but with the withdrawal of Oxbrider has essentially fulfilled that criterion as being not available because that was one of the reasons for not being on that particular therapy. So to some extent, the withdrawal has made it somewhat easier for the patient recruitment perspective.

With respect to the second question around the DSMB, there's no specific safety signal that they're [indiscernible] You may recall, we had conducted previously a first in human study in healthy volunteers. There were approximately 100 healthy volunteers in that study. And there were no dose limiting toxicities or safety signals, acute safety signals of concern in that study. In the initial cohorts, of the PIONEER study, the two, six and the few patients that were enrolled at the twelve milligram dose Again, there were no consistent concerning acute safety signals, or any dose limiting toxicity. So they're going to be passing a broad net looking at all of the safety labs all of the clinical manifestations and so on. But there's no [indiscernible] they'll be looking at. And maybe just add a little bit more color on the first question around Combinator MEZ. I think as Ian said, although l glutamine and chrysolizumab are not broadly used in The U. S. And outside of The U. S. Our estimate are there probably a couple of thousand patients in The U. S. That are on crizolizumab and L glutamine and in the original protocol, patients could not be on either one of those therapies and in our trial But now based on a recent protocol amendment, which we have received approval on from the agency Patients can be on concomitant crizolizumab and will be while being in the study.

So I think that's also an important point to make in addition to the [indiscernible] time. Yes. That's super helpful. And let's just one quick at this one, if I may. When it comes to sort of patient profile, for use of the drug, again, excepting it's very early, you anticipate this would be used after a huge failure because of some of the limitation of not being able to be on both HU and plus year or where do you really see plus Zero Deer fitting in the treatment landscape? Again, accepting that it's still pretty early and we don't have the data yet, but where do you anticipate it being used?

Thanks. Yes. It's a an excellent question, Ted. And I again, it's a really appreciate you asking it. I think yes, so two points I'll make and then I'll turn it over to Ian. You are correct and it is an early study and at this point the agency has said out of an abundance of caution, let's exclude hydroxyurea for this current study. I think we gather more data and And have ongoing discussions with the agency at the end of this year once we have the twelve and twenty milligram in hand, obviously, one of the things that we'll be asking for from the agency is to possibly relax some of that inclusion exclusion criteria? Because many patients are in hydroxyurea and I think from a commercial standpoint, that would be quite challenging if our pivotal study for this drug at some point in the future excluded the use of hydroxyurea. So that's obviously something that we would reengage with the agency on Very similar to the OXprider label that did allow the use of hydroxyurea. In terms of where the drug will be used, I'll just go back to what I said earlier Based on the data that we've generated to data, based on what we know about fetal hemoglobin, with any increase in fetal hemoglobin being beneficial to the patients, even a 1% increase in fetal hemoglobin But once you can get patients to 25, these patients really do become asymptomatic in the presentation their disease as evidenced by the near evolution of the OCs We would expect this drug to be sort of broadly used across many, many patients based on again what we're seeing and what we believe we will see midyear and by the end of the year with the 12 and the twenty milligram Whether it actually becomes first line in place of 12, but the twenty milligram cohort.

Great. Thank you very much for all that color and excited for the data coming up in the middle of this year. It's great. Thanks so much, Ted. Thank you. One moment for our next question. Our next question comes from the line of Gregory Renza of RBC Capital Markets. Your line is now open. Hi, Alex and team. It's Anish on for Greg. Thanks for the updates this quarter and for taking our questions. Just a couple from us. First, how receptive is the FDA to data either historic or currently showing an association between HBF induction and VOC reduction [indiscernible] pipeline, where else outside of hematological diseases might you be able to leverage your Yes, great question. Maybe, I'll turn the first question over to Ian and then I'm happy to talk a little bit about a little bit you a little bit of color into the the second question that you asked.

Yes. So the first one, Anish, is around HBF and the agency view and that's something as Alex mentioned earlier is something that we're directly going to be addressing with the agency. So this is independent of our interactions with them around the clinical data from the PIONEER study, but more generally around the data that exists that support the use of HBF as a surrogate endpoint. And so that interaction is is going to take place this year and we're actively pursuing that. So we'll get some specific feedback from them. As you're aware, I'm sure there haven't been drugs previously approved for sickle cell on the basis of HBF induction alone, but we believe that there are abundant data now that are both genetic epidemiologic pharmacologic and gene therapy that speak to the importance of of HBF induction sickle cell disease and would support its use as a surrogate endpoint. So that's why we are specifically going to be asking the agency about that. Yes. And then Anish, from a BD standpoint, we're always evaluating opportunities. And again, I think you were right to point out that our sweet spot is really benign hematological diseases where there is an unmet need that remains quite high.

What we feel is that the good news is that we don't necessarily have to transact, but we obviously do have a robust balance sheet that we could transact if we found really interesting asset in a rare benign hematologic disease where the unmet need was high, but we certainly don't need to, I think given the high level of interest with sickle cell, but also some of the other inherited aplastic anemias that we're studying for which we'll have our first IND submitted by the end of the year. I think the only other one that I will highlight and this data that Pfizer recently presented at GU. And that's the use of PRC2 inhibitors in prostate cancers. They have a PRC2 inhibitor. It's actually EZH2 inhibitor, not an EED inhibitor like pocereidir, but they have a product called Meverimetestat and we've got the reason I'm bringing this up, we've had a lot of investors sort of ask about this. They showed in eighty patients a marked reduced risk of disease progression and and death by about fifty percent. And so there is some belief that targeting the EED subunit of the PRC2 complex may have some potential advantages over targeting the EDHT subunit, which memvermestat is doing with with Pfizer.

So we're conducting some preclinical experiments now using some xenograft models to evaluate several compounds in our in our library. Going into oncology is not something we're intending to do, but I think given the high level of interest in the use of PRC2 inhibitors in prostate cancer with Pfizer's product and OREZ product. It's something that we are looking at from a preclinical standpoint again, given some of the potential advantages that an EED inhibitor may have over memrometastatin and Oryx product, which are ETH2 inhibitors. Great. Thanks so much for the color. Really appreciate it. Yes. Thanks, Anish.

Participation in today's conference. This does conclude the program. You may now disconnect.