Participants

Alex Sapir; President, Chief Executive Officer, Director; Fulcrum Therapeutics Inc

Alan Musso; Chief Financial Officer, Treasurer; Fulcrum Therapeutics Inc

Iain Fraser; Head of Development; Fulcrum Therapeutics Inc

Joseph Schwartz; Analyst; Leerink Partners

Matthew Biegler; Analyst; Oppenheimer & Co. Inc.

Kristen Kluska; Analyst; Cantor Fitzgerald

Presentation

Operator

Good morning and Welcome to Fulcrum Therapeutics first quarter 2025 financial results and business update conference call. (Operator Instructions). This call is being webcast live and can be accessed on investors section of Fulcrum website at www.fulcrumtx.com and it's being recorded.
Please be reminded that remarks during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 may include statements about the company's future expectations and plans, clinical development timelines, and financial projections.
While these forward-looking statements represent Fulcrum's view as of today, this should not be relied upon as representing the company's views in the future. Fulcrum may update these statements in the future, but it's not taking on an obligation to do so. Please refer to Fulcrum's most recent filings, the Securities and Exchange Commission, for discussions of certain risks and uncertainties associated with the company's business.
Leading the call today will be Alex C. Sapir, CEO and President of Fulcrum. Joining Alex on the call are Alan Musso, Chief Financial Officer. After providing updates on the company's key programs, there'll be a brief Q&A in which the bulk management team will be available for questions. With that, it is my pleasure to send the call over to Alex.

Alex Sapir

Thank you, Olivia, and good morning, everyone, and thanks for joining us today. So before jumping into the updates for the quarter, I just wanted to take a moment to welcome Dae Gon Ha, the newest member of the Fulcrum management team, as our Senior Vice President, Head of Strategy and Business Development.
Now Dae Gon is no stranger to Fulcrum nor to the sickle cell space. For the past five years, Dea Gon was an equity research analyst at the banking firm Steeple covering Fulcrum. Dea Gon, whose first day with the company is today, will be focused on overall corporate strategy and business development here at Fulcrum as we continue our efforts in sickle cell disease and other benign hematological conditions.
So now let's turn to the updates for the quarter. The past several months have been an exciting period for Fulcrum as we've continued to make good progress with our lead program Pociredir , which is currently enrolling in a phase 1b trial, a trial that we call Pioneer for the treatment of sickle cell disease, an inherited blood disorder afflicting approximately 100,000 people in the US and approximately 4.4 million people worldwide.
I am pleased to announce that we've completed enrollment in the 12 mg cohort cohort 3, with a total of 16 patients enrolled and plan to share results of this cohort in early Q3. These data will include key baseline, patient characteristics, adverse events, magnitude of HBF induction, and changes in other important hematological parameters measured throughout the study.
Let me spend a bit of time providing some details on these 16 patients. The majority of these patients have come from sites in the US, with the remainder coming from a single site in South Africa. Their median fetal hemoglobin level at the start of the study was 7.7%, with a mean value of 7.6%. To date, no patients have discontinued from the study, and we continue to see greater than 90% adherence to the once a day oral drug regimen.
Furthermore, we're pleased to report that the data monitoring committee for the Pioneer study, after reviewing interim data from the 12 mg cohort, recommended that we continue the study as planned with the initiation of the 20 mg cohort cohort 4, which is now underway and currently screening patients. We remain on track with our plans to report data from cohort 4, the 20 mg cohort, by the end of 2025.
And we continue to believe that inducing fetal hemoglobin is the optimal strategy for treating sickle cell disease. Evidence for this approach continues to grow as highlighted by not only the recently approved gene therapies, but recent data analysis showing that even modest increases in fetal hemoglobin correlate to reduced disease severity.
Specifically, a recent data analysis that was presented at as last December shows that for every 1% increase in HBF, there was a 4% to 8% reduction in Vaso-Occlusive Crisis or VOCs. These VOCs occur when sickled red blood cells prevent oxygenated blood from getting to the tissues, resulting in debilitating pain, often requiring hospitalization or visits to the emergency room.
Additionally, fetal hemoglobin levels in the mid 20% range have shown in your abolition of these VOCs that I spoke about. Based on Pociredir mechanism of action and the data that we have previously disclosed, we believe that Pociredir has the potential to provide a differentiated therapeutic option for people living with sickle cell disease.
And we look forward to providing important clinical data this year to further validate our potentially transformative approach with Pociredir. At the upcoming European Hematology Association Meeting, or EHAF for short, which is being held in June in Milan, we have two abstracts that have been accepted for poster presentation.
Those abstracts include preclinical target engagement and reversibility of gene expression data with Pociredir, as well as clinical data from our previously completed phase one healthy volunteer study. Now beyond Pociredir, we continue to advance our earlier stage development program for the potential treatment of inherited aplastic anemias.
Such as Diamond-Blackfan Anemia or DBA, Shwachman-Diamond Syndrome, and Fanconi anemia. We plan to submit an IND for DBA in the fourth quarter of this year. And with that overview, I will now turn it over to our Chief Financial Officer Alan Musso to run through the financials. Over to you, Alan.

Alan Musso

Thanks, Alex. I'll now go over our results for the quarter ended March 31, 2025. Our research and development expenses were $13.4 million for the first quarter of 2025 compared to $19.8 million for the first quarter of 2024.
The decrease of $6.4 million was due to the discontinuation of our losmapimod program and the global development cost sharing reimbursement under the Sanofi collaboration, partially offset by increased costs related to the advancement of the phase 1b pioneer trial of pociredir.
The general administrative expenses were $7 million for the first quarter of 2025 compared to $10.1 million for the first quarter of 2024. $3.1 million decrease, primarily due to decreased employee compensation costs as a result of the reduction in workforce implemented in the third quarter of 2024.
Net loss was $17.7 million for the first quarter of 2025 compared to a net loss of $26.9 million for the first quarter of 2024. And turning to the balance sheet, we ended the first quarter of 2025 with cash equivalent, and marketable securities of $226.6 million compared to $241 million as of December 31, 2024. The $14.4 million decrease is primarily due to cash used to fund the operating activities.
And finally turning to cash guidance based on our current operating plans, we continue to expect that our existing cash equivalents and marketable securities will be sufficient to fund our operating requirements into at least 2027. And with that, I'll turn the call over back to you Alex.

Alex Sapir

That's great. Thanks, Alan. So to conclude, Fulcrum is off to a solid start in 2025, and we're very much looking forward to delivering two important data releases this year with the Pioneer trial. So with that overview of the business and the financials that Alan went over, Olivia, let's go ahead and open it up for questions.

Question and Answer Session

Operator

(Operator Instructions). First question coming from the line of Joseph Schwartz with Leerink Partners, sir your line is now open.

Joseph Schwartz

Great, thanks so much. Congrats on all the progress and hi to Dae Gon. Look forward to working together again. I was wondering if you could talk some more about the quantum of data you expect to report from the 12 mg cohort of Pioneer mid-year.
What range of follow-up duration do you anticipate we'll see for the 16 patients who've been enrolled, and will we get any data on the markers of homolysis in addition to fetal hemoglobin data for these patients?

Alex Sapir

Yeah, great question, Joe, thanks for asking it to answer that, I will turn that answer over to Iain Fraser, our Head of development who is actually was in the room, but it wasn't introduced at the outset of the call.

Iain Fraser

Yeah, thanks, Alice. Maybe for the first, the second part of your question, Joe markers of hemolysis, yes, we'll be providing hematological parameters, the blood counts, bilirubins, and so on, as indicators of hemolysis. With respect to the first part of your question, we will have all the data for all16 patients on the treatment.
Phase of the study, so that's the three-month treatment duration and then a subset of the patients with the four week follow up after that. There probably will not be all 16 for the full four weeks based on the data cut, but we will have a subset of those patients.

Joseph Schwartz

Great, thanks. That's super helpful. And then, I guess, does the observed dosing provide you with a specific data on the number of doses that patients are receiving real time, and do you happen to have any of that data handy that you can share with us?

Alex Sapir

Yeah, Joe, is this sort of related to the 90% adherence number that we referenced in our opening remarks?

Joseph Schwartz

Yeah, I'm just, yeah, I guess any, is there any more colour that you can provide on, the timing of the doses? Are they all within the prescribed time frame and I guess how many doses have occurred to date?

Alex Sapir

Yeah, it's a it's it's a great question, Joe. I appreciate you asking it so let me give up maybe a little bit of background. So just for everybody that's on the call, it is an oral once daily dosing and the way that we're able to capture the adherence rates is not through the more traditional kind of pill counts at the end of the month where the patient comes in and gets their next bottle.
It's really using this AI tool that we mentioned and that is listed in our investor presentation AI cure and this is something where the actual patient has to sort of. Register themselves on this AI tool show that they've actually put the drug in their mouth, have swallowed it. They then have to open their mouth to show that the that the drug is gone and then and then we get reports.
I wouldn't necessarily say on a real-time basis, but we get them in a very sort of timely manner as. Do the as do the sites as well and so that's really where that where that 90% that's where that 90% number is coming from, not really from the more traditional ways that people measure adherence to drug around pill counts, anything else you want to add to that?

Iain Fraser

No, other than that, the patient selects the time of day that they want to take their medication, and the app will remind them at that time, so everything's built around that, time of day that that they're taking it, and that gets captured as well.

Alex Sapir

Yeah, and we, so we certainly can capture that joe, assuming that they're using the tool which we know they are in. Greater than 90% of cases so we can actually determine are they actually taking it exactly at 8 o'clock every day for the full 84 days or not I don't have that data handy and I'm not, we haven't really discussed whether that's something that we'll be presenting when we share the data in early Q3. Does that answer your question?

Joseph Schwartz

Yeah, that's excellent. We're looking forward to your updates this year. Thanks for the inputs.

Alex Sapir

Yeah, thanks so much, Joe, for the questions.

Operator

Thank you. Our next question coming from line of Matthew Biegler with Oppenheimer, you let us know.

Matthew Biegler

Oh great. Hey everyone, I'll send my congrats as well. Thanks for the updated color here. The baseline HBF is a bit higher, I think at 7% than we anticipated given like the severity of disease for these patients at entry. So number one, do you think you've gotten a representative sample of the broader demographic you're going to be trying to treat here when we do get the data and number two.
Do you think poster should work equally well or perhaps even better in patients with higher baseline HPF?

Alex Sapir

Yeah, great question, Joe. Sorry, great question, Matt. Thanks for asking them. Yeah, let me maybe just comment a little bit on your first sort of comment that it was a little bit sort of higher than many people had had expected. I think that what we were hearing in our normal course of conversations with investors is that because this was a more severe patient population, I think some were worried that, you were seeing.
A baseline fetal hemoglobin in the very sort of low single digits, and if they are in the very low single digits, it's going to be very sort of difficult to get them, to a number that that people can get excited about. So I think when we saw what the baselines were at, 7.7% for the median and the mean value.
7.6% we thought it was important to sort of share that with folks because again I think many people were thinking that boy these baseline fetal hemoglobin levels could be extremely low given the severity of the patients that were enrolling and then maybe in answer to your other two questions, let me turn that one over to Iain.

Iain Fraser

Yeah, I would think Matt, that that in the General population with larger numbers, those that have the more severe phenotype will tend to have lower baseline fetal hemoglobins. We have a small sample size here, at the moment and spans a range of those baselines.
I don't think there's anything unexpected around that, and as Alex said, we thought it was helpful to provide that additional bit of colour, leading into the data readout. With respect to your other question about, responsiveness, I think at the moment, we don't have any reason to believe that your baseline level of HBF in and of itself determines your response to [Boeria].
And we've certainly seen from the initial 16 patients in all that that some at the low end had a pretty robust induction of HBF in response to drug. I think what is fair to say is that if you're starting very low, where you eventually max out at steady state on therapy may be. At a lower absolute fetal hemoglobin than if you were starting at a higher level, but I think we need the fuller data set to be able to comment further on that.

Matthew Biegler

Okay, awesome. That makes a lot of sense. If I could just maybe squeeze one quick one minute on the guide going from, I guess mid-year to early 3Q, is that just kind of the nuts and bolts of the execution of the clinical trial, or you actually want to get more follow up on, potential disease modification and points, such like that. Thank you very much.

Alex Sapir

Yeah, Matt, I think it was really just more the execution of the trial. We thought that obviously having more patients versus less patients would be better. The fact that we've enrolled 16 and as Iian said, we'll have the full treatment data for all of those 16 patients at the at the end of Q3. So that, sorry, at the beginning of Q3. So that was really, I think the reason that we tighten that guidance, but still that guidance has always been in the sort of mid, mid-year range.

Operator

Thank you. Our next question coming from the line of [at work and help with coffee summer] your line is now open.

Great thank you. Thank you very much for taking the call and I apologize, I'm bouncing a little bit between calls today, but I just want to get a sense for and I apologize if this was asked, but what is, what's a win for you guys from the 12 week data?
Obviously we saw somewhere around 10% there's going to be some differences in terms of the patients who are enrolled maybe the baseline, he will be different, but what are you guys really focused on from that data set to know that this is, working? And in the ballpark you're looking for.

Alex Sapir

Yeah, thanks for the question, Ted. I'll start and then I'll turn it over to Iain for any you know additional color as we've said in the past and as we said in our opening remarks, I think that any increase in fetal hemoglobin is beneficial to the patients and even something as small as a 1% increase can lead to a 4% of anywhere from a 4% to 8% reduction in VOCs.
We also know that based on Drugs that have been approved for the treatment of sickle cell, VOC reduction somewhere in the sort of 25% to 50% range is considered clinically meaningful for the patients and that has been the basis of approval. So where you sort of net out in that 4% to 8% range, you could easily have single digit, absolute single digit increases in fetal hemoglobin.
Compared to where the patients were at baseline and that can be clinically meaningful, certainly for the patients. Once you get to that 25% range, that's really where it becomes transformative for patients. Maybe let me stop there and see what additional colour Iain wants to add.

Iain Fraser

So I think Ted, you alluded to what we had seen before and we're looking to see with, as we broaden the numbers of patients in the cohort, that we reaffirm that magnitude of induction and as Alex said, the mid-single digit percent increases in in fetal hemoglobin are expected to be clinically meaningful.

Great. Excellent. Thanks and thanks guys. It really makes a lot of sense. Look forward to the data

Alex Sapir

Yeah, thanks.

Operator

Thank you. Our next question coming from the line of Kristen Kluska with Cantor Fitzgerald, your line is now open.

Kristen Kluska

Hi, good morning, everybody. Very encouraging to see you ended up with 16 patients in this cohort, and that enrollment overall seems to be going a lot faster than a lot of us expected. How much of this, in your opinion, could just be attributed to the loss of Oxbryta and different dynamics or how much of it is attributed to getting more sites on board?

Alex Sapir

Yeah, Kristen, it's Alex. Thanks for the question. I think it's a combination of both, and when you say getting sites on board, I think what we have now is we've got the right sites on board and what I mean by right sites is these are sites that we know tend to treat older patients that maybe have more severe disease.
Either 4 VOCs over a 12-month period of time or two VOCs over a six-month period of time. So these patients do tend to be more severe. So I think that, part of that is driven by the fact that we've got the right sites on board. I think part of it is also driven by the fact that Voxelotor is no longer available and obviously the patients that were on.
Voxelotor obviously were very interested in actively managing their disease. So once they had to go off, I think that many of those patients were going back to their physicians and saying, what else is what else is available. And then I would say that the third factor is just kind of overall excitement.
And momentum around fetal hemoglobin induction as really what we believe is the path forward to really potentially see transformative treatment options for these patients and with us being very much sort of at the forefront and leading that charge.
Physicians get excited about the drug, they start, get excited about the trial, they start the patient, they hear, positive sentiments from their patients and that just sort of feeds even greater success and greater enrollment into the, in, into the study Iain anything you want to add there?

Iain Fraser

Well, the only additional bit of colour would be, I think we've articulated previously how getting some of these sites that are best matched to this patient population takes a long time to get those sites up and running, and there is that lag phase.
And I think what we're seeing is that lag phase being overcome, those sites being activated with the right sites being able to recruit the patients and that's really helped with the recruitment in the study.

Kristen Kluska

Okay thanks and I know you're you talked about that you don't currently have reason to believe that baseline levels will determine your responses but has there been any work or research done to understand why certain patient populations may present as more severe and why these patients don't respond to other therapies that are part of your inclusion exclusion criteria.
And I think ultimately where I'm trying to go with my question. If you're able to show response in a population that's already deemed to be quite severe and tougher to treat with any intervention, how does that help us understand how the data can translate potentially to a more traditional all-comer's population.

Alex Sapir

Iain you want to take that?

Iain Fraser

Yeah, that, that's a great question. I think there are lots of components there, Kristen, on the one hand, the, relationship between, the underlying genetics and the severity manifestations of the disease. And it, and HPF is obviously a big contributor to that, but there are other components related to that as well. And then secondly is the aspect of responsiveness to therapy as being able to provide benefit to those patients.
And I think that's going to be different for different therapies. Different therapies will have different. Reasons for responsiveness or non-responsiveness. I think as we move through our clinical program, those are things that we're going to be looking for. Are there key issues that we can tease out as determining responsiveness or not, and translating to benefits.
So I think that's an important piece of it. With respect to the translatability to the less severe patient population, we do have data from the initial 16 patients in the study, who were less clinically severe at the outset, and while we don't have really clinical data because it's a short study, we do have their HBF responses and those, as I think everyone knows, have been very encouraging.
So we certainly expect to see that responsiveness there and even at the high end of baseline fetal hemoglobin, small increments, even on top of relatively high baselines are clearly associated with benefit as well. So we would expect to see that translate to.

Kristen Kluska

Thanks Alex and Iain.

Alex Sapir

Yeah, thanks, Kristen. Next question, operator.

Operator

Thank you. And as reminded to ask a question, please press 11. Our next question coming from the line of Gregory Renzo with RBC Capital Markets. The line is now open.

Good Morning Alex and team. It's Ani on for Greg. Thanks for the updates this quarter and for taking our questions. Just a couple from us first, given the shifts at the FDA, how are you thinking about the impact to Pay's broader developments such as on endpoint selection, HBF as a surrogate marker, which I know you've talked about before, and even the overall development timelines? What's your take on the current set up with regulators? And then just quickly in your deck you note novel HBF inducers in your discovery pipeline. Could you share how you're thinking about differentiating from other mechanisms in the landscape such as wis degraders, DNM-T1 inhibitors, etc. to bring that novelty? Thanks so much.

Alex Sapir

Yeah, two really good questions, and I appreciate you asking them maybe to answer those, let me turn this over to Iain.

Iain Fraser

Yeah, and I think what we'll be doing as we've articulated previously is that at the end of the 20 mg cohort, at the end of the phase 1 study, we'll be interacting with the FDA in the end of phase one interaction. And I think that'll be our opportunity to get a gauge on their thinking as we discuss plans for the next study there.
So that, so that's an upcoming interaction which is planned and which we expect will occur at the end of the 20 mg cohort. With respect to the other HPF inducers, I think we're looking more broadly and agnostically at compounds that are able to induce HPF.
I think it's early days in the clinic for some of the other inducers that have just entered the clinic in the last year or so, including, as you mentioned, which degrades and the Which ZBTB 7A degrader from BMS and GSK's DNMT1 inhibitor. We don't have any clinical data from those as yet, but we'll be monitoring those closely and looking for alternative ways of inducing HBF.

Great, thanks so much

Alex Sapir

Thanks Anish

Operator

Thank you. And I'm showing no further questions in the and Queue at this time and this concludes today's conference call. Thank you all for your participation, and you may now disconnect.