Fulcrum Therapeutics, Inc. (FULC) Earnings Call Transcript & Summary

Thanks, everybody. Welcome to the Bank of America Healthcare Conference. I'm Tazeen Ahmad. I'm one of the senior SMID biotech analysts here at the bank. It's my pleasure to have our next presenting company, Fulcrum Therapeutics, with me. Sitting on stage are several members of the management team. We've got Bryan. We've got Judith. We've got Paul. I'll let you introduce yourselves. And then maybe, Bryan, could you give us a couple of minute overview of the company, your platform and some of your key recent updates? And then we can go through into Q&A if that works.

Yes, absolutely. That would be great. So Bryan Stuart, the CEO of Fulcrum.

I'm Judy Dunn, President of R&D.

Paul Bruno, the Executive Director of Corporate Development.

Yes. So in terms of a high-level overview, at Fulcrum, our mission is to deliver medicines that are disease-modifying for people suffering from rare genetically defined diseases. So this discovery approach that we started the company with has, in a very short period of time, led to 3 clinical programs that have the potential to be disease-modifying as well as 2 collaborations. So our most advanced program is a drug called losmapimod for FSHD. FSHD is actually the second most prevalent form of muscular dystrophy. It's a devastating and relentless disease that affects about 500,000 people worldwide. And despite the prevalence, there are no therapeutic alternatives. There's nothing else in the clinic. And we uniquely identified the relationship between this program losmapimod and its ability to treat the root cause of the disease, which is the aberrant expression of DUX4. We had a Phase IIb trial that read out last year that we were very excited about in that it showed statistically significant and clinically meaningful benefit in muscle health, in function, in strength and patient-reported outcomes. And that enabled us to get alignment with regulators as we did at the end of last year and agree on a primary endpoint for a Phase III trial, which we are planning to initiate this quarter. Our second program, which we're equally excited about, is FTX-6058. And that is an oral HbF inducer for both sickle cell disease and non-sickle cell hemoglobinopathies, including beta-thal. So there's a tremendous amount of data that exists from people who have a condition called hereditary persistence of fetal hemoglobin. And these are people who have sickle cell trait, but they also have a second mutation, which causes their HbF to be elevated. And what this clearly shows is that the only way to be able to treat all of the underlying symptoms of sickle cell disease is by inducing HbF. So we uniquely identified a target. We used our own medicinal chemistry and created a compound, which is now in a Phase Ib trial with -- for people with sickle cell disease, where we are trying to induce HbF. And if we are successful in doing that, we believe this has the potential to be a truly transformative therapy and one that can dramatically change the landscape for sickle cell disease. So very excited about those programs and our approach.

So let's start with 6058. It's a very interesting approach that you've chosen in an area of high undermet need. There's a lot of companies that are trying to work on sickle cell. Maybe, Bryan, if you could spend a couple of minutes telling us about how you think your approach is particularly differentiated.

Yes, absolutely. And I think most importantly -- and you're exactly right. So sickle cell disease is unfortunately a devastating disease that affects millions of people globally, over 100,000 in the U.S. And unfortunately, there are very few therapeutic alternatives today. And I think what's very unique about our approach is the vast majority of drugs that are in development for sickle cell disease are looking to treat only select symptoms. So either VOCs or anemia, the only mechanism, as I mentioned, that has this very strong data supporting its ability to treat everything is by inducing HbF. There are no oral HbF inducers in development. The only HbF-inducing mechanisms, if you will, are gene editing. So that proves to be great validation for our approach, but obviously, gene editing is extremely invasive and cumbersome. So the -- we're excited about the opportunity to potentially do this with a once-daily pill, and it really is differentiated for both everything that is approved today and everything else that's in development, and we're very excited about the approach.

Okay. For some time, there have been comparisons to the approach that you've undertaken to what Imara was doing. And so why do you think that was the wrong way of looking at it?

Yes. So I think one of the things that we are most excited about is a combination of preclinical data that we've generated so far as well as our Phase I healthy volunteer data that we shared last year. And our preclinical data has shown a robust increase in both HPG mRNA as well as protein across a number of different assays, including CD34-positive assay, Townes mouse model, wild-type model. We saw a similar induction in mRNA in healthy volunteers. I think the CD34-positive assay is a particular interest in that we've profiled a number of other mechanisms that either have tried to induce HbF -- some of them were successful. Some of them were unsuccessful. The PDE9 inhibitor was something that we tested. That was a [ MARS ] program. We did not observe any HbF induction in that assay. And I think that's what's consistent with what was observed in the clinic. So I think we're very encouraged by the fact that based on what we've seen in the translatability of this assay before, it seems to have translated very well. I think at a high level, though, we certainly -- as we said, the opportunity to induce HbF with a small molecule, we think, would really be transformational.

Right. So we're all excited for your upcoming update for your program. Can you give us a sense of what to expect on that Phase Ib update, what in your mind would be clinically meaningful and what the next steps would be?

Yes, absolutely.

Sure. I'll take that. Our Phase Ib program, I think, to understand it, what I want to do is just talk a few more seconds in terms of what Bryan already expounded upon in our Ia program. We're really doing a deliberate study of the interactions between exposure, mRNA and hopefully, ultimately, protein as well as target engagement. So when we did our Phase I study, we built a fairly robust pharmacological model. So using quantitative pharmacology to really understand these relationships, what's the relationship between exposure, target engagement, mRNA in healthy normals, understanding the kinetics as well as the scope of the changes. In this next study, we will add HbF to that, put it in the model and really hope to understand 2 things: one is what is the kinetics of the onset, hopefully, when we see HbF; and then secondly, how high are these changes. What we know from the literature, as Bryan already spoke to, from the literature, from gene editing, from KOLs, the focus for the program and the goal for the program ultimately in a therapy is to get to a 5% to 10% increase in HbF over the baseline. That will be transformative. Now in this first study, we will look at a dose of 6 milligrams. We picked that because in the early healthy volunteer study, that was a reasonable dose that did show us target engagement, and it did show us meaningful amounts of mRNA. So by taking this dose into patients with sickle cell disease, what we'd look to see in approximately a month is some protein induction, some. If we see that, that is transformative for the program, and it is proof of concept. We're also going to look at 3 months. Now when you look at the other mechanisms of action that are increasing HbF, they get to maximal levels in 3 to 5 months. So 3 months might not be maximal for us, but it will be sufficient for us to take this data, take the data from our pharmacological modeling and be able to identify a clear path forward for the program to be able to deliver that transformative level of HbF in increasing that 5% to 10% over baseline. So for us, this will be really instructive in terms of proof of concept, first time we're seeing protein production in patients, then also that clearly defined pathway to what a hopefully single dose will be for a registration trial.

Okay. That was crystal clear. Thanks for that, Judith. Now one thing that I'm curious about is if it takes anywhere from 3 to 5 months to get to that maximum level, why take a look at 3? Why not wait until like 6 months?

So 3 months will be sufficient. So just as I outlined, because we really do understand those kinetics in terms of that target engagement, that time to onset, what we wanted to do was to build a model to help us predict both the kinetics as well as the increase. We believe that we will understand enough about these relationships so that at 3 months, if we are at that 5% to 10% increase over baseline, phenomenal. But we don't need to be there at our very first dose. What we need to understand is what do those relationships look like, not just the protein, but what is the target engagement, what is the mRNA, what is the kinetics of those reactions. We'll be able to then look back at our model and say, all right, now we know what to do next.

Okay. So that's important maybe to level set expectations. So you may not get to that 5% to 10% at a 3-month view. So then what other data points will you talk about when you show us that Phase Ib data that will help us better appreciate that proof of concept that you just mentioned?

Yes. So we'll be including a number of other endpoints in the study. We haven't disclosed which endpoints we will be sharing at the EHA disclosure. But broadly, we want to be able to demonstrate HbF increases, also potential biomarkers that suggest that we're addressing the homolysis associated with the disease, but we need to look at the data and determine which ones we'll ultimately share.

I guess I would also add, I think one of the things that we're most excited about and the field is most excited about is between hereditary persistence of fetal hemoglobin, all of the literature that exists with HbF, what we're now seeing with gene editing there is such a validation in terms of if we're able to see HbF increase, then we know the benefits in terms of reduction of key symptoms. All of those things will follow. So as Judy said at this point, and the reason that we wanted to share even initial data is back when we shared our healthy volunteer data, we were very encouraged by the increases in mRNA, but we were not dosing long enough to be able to observe increases in protein. And this should be sufficient time to see if we are, in fact, able to increase HbF and do so robustly.

Okay. Maybe it's too early to be asking this question, but as you try to project forward, where in the treatment regimen do you think this product could fall, especially in relation to hydroxyurea?

Yes, absolutely. And that's certainly something that we've spent a lot of time talking to KOLs, talking to physicians and asking them the question, HbF is very much -- it's very well understood, but what do you need to see not for you to utilize 6058 but for it to be transformational and standard of care. And we consistently -- as Judy said, ultimately, in a therapy, 5% to 10% is the response that we get. And that's supported by literature. So we're very encouraged by that triangulation. We believe that if we're ultimately able to achieve that in a therapy that this will be standard of care. One of the things that we want to look at in the Phase Ib trial is to understand if patients are on HU, how these 2 therapies fit together. As we looked at this preclinically, we saw additivity. Obviously, we'll want to confirm that. Unfortunately, while HU has certainly efficacy for some, there are meaningful safety and tolerability challenges. The efficacy is -- does wane over time. And as a result, many people unfortunately cycle through HU. So the opportunity to potentially develop something that would be more robust in terms of efficacy is very exciting for us.

Okay. So what would be sort of your plan for next steps after you show us the Phase Ib? Will there be another 6-month view? Would you then -- if the data looks the way you expect it to look, just go ahead and move to the next phase of development? What are your plans?

Yes. So our plan is to early next year being a registrational trial, but a single dose in Ib is not going to be sufficient. So as I stated, really what we need to do for ourselves in order to select the appropriate single dose for a registration trial is to really understand sort of quantitative pharmacology behind us. So we have planned for up to 2 more cohorts of approximately 10 patients, and we'll utilize that plus the healthy volunteer data to select a dose and then move into a registrational trial next year, early next year.

Okay. Any idea what that registrational study should look like?

Certainly, we've done some thinking about that, and it really goes back to the points that Bryan has stated earlier, and it is really the preponderance of data that supports HbF as an endpoint or at least a surrogate. That 5% to 10% increase in HbF over baseline, we know, is well validated. And that's what the regulators globally look for when they look for a surrogate endpoint. Does it move in the right direction? And is it predictive of value? And certainly, with HbF, we have that data. So you might imagine a program that initially looked at this HbF level but then continued to then look at clinical outcomes such as VOCs, perhaps acute chest syndrome, the variety of symptoms that are associated with sickle. And I think we're in a particularly good position here because early on, Bryan stated that this is the only mechanism that has been shown to cover all of those symptoms. So we have some optionality here. So it might not be just VOCs. We do have a lot of ability to show true benefit to patients across a variety of symptoms, but first and foremost, talking to regulators about the utility of HbF changes as surrogate.

Okay. You mentioned VOC. So let's talk about that for a second. It's going to be too early probably for you to give us any color on VOC impact. But how predictive is HbF movement on what to ultimately expect on VOCs?

Yes, it's very predictive. And there's a few different data points that kind of point to that. As Bryan alluded to, we hear from KOLs that 5% to 10% increase in HbF over baseline levels, that will have a very meaningful impact on VOCs. We recently conducted a systematic literature review as well, pointing to 3% to 7% increases in HbF having dramatic effects on VOCs. I think the other point to highlight is emerging gene editing and gene therapy data point to mid-teens as being the benchmark to see 80% to 100% reduction in VOC. And so all of this is triangulated around that 5% to 10% that we consistently hear from KOLs in terms of having broad clinical benefit.

How important is it to be as high as possible on the VOC reductions? Is there a threshold that you reach, after which it doesn't really matter so much anymore?

Yes. So once you get above 20%, the literature suggests that you see complete reduction, but recognizing and getting into the teens, in between 10% and 20%, you're going to have broad clinical benefits beyond just VOCs. You're going start to see reductions in things like acute chest syndrome, transfusions, stroke risk. So there's potential for broad benefit here beyond just VOCs.

Sure. Okay. And do you think that if approved, this would be applicable to the entire SCD market?

So that is certainly our hypothesis going into this. So that's certainly one of the things that we want to understand in terms of different genotypes, any type of variability. But we believe that the Phase Ib trial is intended to be sufficient in terms of the number of patients that are enrolled that we're going to look to understand that. But that's really informed by our preclinical data. And as we looked preclinically, we saw a very consistent response across every sample that we looked at in our CD34-positive assay. So that's encouraging, and we'll obviously look to the clinical data to really understand that.

Okay. What is the status of the non-SCD hemoglobinopathies right now?

Yes. So we intend and we believe certainly that this mechanism has the potential to be -- have utility in non-sickle cell hemoglonopathies, including beta-thal. We announced at our earnings earlier this week that we plan to initiate that trial now in the second half of this year. It's still a focus from our perspective and one that we're very excited about. At the same time, our primary focus for this program is going to be on executing the Phase Ib trial in sickle, and as Judy said, really trying to actively think about and design a registrational trial that can begin in 2023. So we'll look to balance both with sickle being our primary focus.

Okay. How does that market opportunity maybe differ from sickle?

Yes. So the majority of the patients are located in Europe, where obviously, for sickle cell, there's a meaningful population in the U.S. In terms of the opportunity, the big key point here is transfusions. And so we do know that with increasing HbF, we can reduce the transfusion burden associated with these patients. So certainly think there's a tremendous benefit, both for nontransfusion-dependent patients as well as transfusion-dependent patients. Beyond transfusions, it's not uncommon to experience things like pulmonary arterial hypertension, experience ulcers. So there's a lot of other opportunities to provide benefit even to those nontransfusion-dependent patients that are experiencing ongoing anemia.

Yes. Do you think that whether it be sickle or beta that these are underdiagnosed conditions right now?

Potentially, newborn screening is pretty common. So I think we have a good idea of the prevalent population. But there's always an opportunity to identify more patients.

Okay. So have you talked about what size your registrational study would need to be?

No, we have not talked about that. As I said, we're still thinking through this just in terms of, first, the dose but then those endpoints. Of course, we would have a significant number of patients to not only power for HbF but for a clinical outcome as well as to have a reasonable-sized database.

Right. And how easy do you think it is to enroll patients in sort of a study like this?

So we've got -- we have some experience now enrolling this population, and it is an interesting population in that there are a number of societies for sickle cell disease. There are also a number of community-based organizations that are really one of the key places to outreach for patients here. And that is a little bit different than all of the other therapeutic areas that we have brought experience in. So I think the organizations themselves, the community-based organizations as well as the fact that there is still a real unmet medical need here and patients do want a better therapy, and the HbF story is very easy to understand in terms of the literature that's available, so we think not only the key opinion leaders but the physicians are going to be able to talk to patients about the broad benefits of this once-a-day pill. And so we think that all of that together will be able to help us drive enrollment into our studies.

Okay. Perfect. Maybe let's switch gears to a different program, FSHD. So that was the first indication that you and I had talked about way back, losmapimod. can you maybe, Bryan, give us a quick summary of the history of that molecule and the events that led up to your discussion with FDA and subsequent announcement of your Phase III program?

Yes, sure, absolutely. So as we mentioned, one of the first programs that we focused on at Fulcrum and really a disease that represented a good fit for our discovery approach is FSHD. And the reason why it represented such a good fit is, unfortunately, it's a very large and devastating disease, as I mentioned, the second most prevalent form of muscular dystrophy. But there's nothing approved. There's nothing used off label, and there's not even anything else in the clinic at this point. So we uniquely identified with our discovery approach a target that robustly preclinically reduces DUX4-driven gene expression. That is the root cause of the disease, and that is what causes essentially fat to infiltrate muscle. We were in a unique situation because we do our screening in a non-biased way, but there is actually a chemical matter associated with this target. So we were able to in-license a compound losmapimod that had been dosed in over 3,500 subjects. And as we think about a rare disease and as we think about a chronic disease, it put us in a very unique position. So we then transitioned into the clinic into a Phase IIb trial. And our primary endpoint was a molecular biomarker. So it was a DUX4-driven gene expression via a needle biopsy. But we also included a number of other endpoints related to muscle health function, strength, patient-reported outcomes. I think to our great surprise, over 48 weeks, we observed not only patient decline with placebo but a clear separation on a number of endpoints with losmapimod. So fat infiltration nearly stopped. Patients had a differentiation in strength, in function and in patient-reported outcomes. So that put us in a position to then go meet with regulators, both in the U.S. and outside the U.S., which we did at the end of last year. And we got alignment on reachable workspace, which is one of these measures of function where we achieved a clinically meaningful and statistically significant benefit as the primary endpoint in the Phase III trial. So that puts us in a position where we're able to replicate many of the elements that were successful from the Phase IIb trial. So this will be a 48-week trial, randomized one-to-one, reachable workspace as the primary end point. And I think we're very excited. Certainly ups and downs with any program, but to be in a position now that we have the potential to enter a registrational trial and move forward a therapy that could have such a big impact on so many people, we're really excited to get this started.

Yes. And so with all rare disease trials, the question always arises of how long do you think it will take to enroll such a study.

Absolutely. And that is the same question we asked ourselves and certainly the same question that we asked ourselves before we initiated the Phase IIb trial. And you said it very well. In rare disease, there's always that until you execute on a clinical trial, particularly in disease like FSHD, where there's been relatively limited development, you just never know. We went into that thinking that because of the unmet need, the devastation of the disease and the lack of competing trials that patients would be very enthusiastic about the opportunity. And they were. So we were able to fully enroll our Phase IIb trial in less than 6 months. We had a tremendous amount of interest in the trial. And now as we execute on the Phase III, it will certainly be larger. But we're able to go back to those -- many of the sites that we utilized, adding some more sites, and we think that will put us in a position to execute on this very efficiently.

Okay. Now can we spend a minute talking about the endpoint, the reachable workspace endpoint? So because this is a rare disease, it may not be a term that a lot of people know well or would have a sense of what's good and what's not good. So I guess what's your view of the difficulty of achieving this endpoint? Because there are other types of endpoints, I don't know, 6-minute walk, for example, which is constantly now being discussed for other programs, being viewed as very subjective, not reliable. How would you contrast something like this to that?

So in the Phase II study, we really did look at a number of endpoints that were measured a function because that's what regulators care about, how do patients feel, function and survive. And we looked at reachable workspace, which is a measure of upper extremity function. Now this is a disorder where fat infiltrates muscle. People lose functionality. Think about losing functionality in your arms. So you can't reach over your head. You can't wash your own hair. You can't reach in front of you. So you can't grasp. So patients realize these changes, and they see that for every percent of space they can't access, that is one step closer to loss of independence. And so with reachable workspace, this is a quantitative measure of function. It's measured in an unbiased way. So you made a good point in terms of some of these endpoints suffer from recall bias. They suffer from placebo response. This is a measure where patients are seated in a chair, and they move their arm into different quadrants. And this is captured by a video camera and measured. So the bias of a radar, the bias of a patient is taken away. It's also very highly sensitive to change. But most importantly, how do we understand this, this measure is also correlated with activities of daily living. So another scale that people in the field might know more about is the Neuro-QoL, which is the neuro quality of life. And this is a measure of a self-report measure of how you're functioning, but it does suffer from these recall biases. And over the course of 48 weeks, it's going to be very tough for patients to reliably remember how they were feeling 10 or 15 or 20 weeks ago. But with this camera seated in a chair, this performance index, it's very easy for patients to understand how to do it. Patients very quickly understood the clinical relevance. It's very intuitive. If you can move your arm through all of these quadrants for a longer period of time, you're going to be able to perform activities of daily function for a longer period of time. So though it might be unfamiliar, it's been used in a number of clinical trials. We'll be the first ones to register with it. But when we talk to the patient community, the word intuitive is the one that comes to mind because they very well understand how meaningful it is for them to be able to maintain use of their arms.

Okay. Yes, that makes a lot of sense. Just quickly on the competitive landscape, how do you see FSH?

Yes. So we are the only program in clinical development right now. There's a number of other programs preclinical right now. Encouragingly, everyone's focused on the same target, reducing DUX4. We showed very potent activity, both in vitro and in vivo. And so we feel we're a number of years ahead of our competition and obviously very much focused on this functional endpoint in this pivotal trial, which I think will be very exciting for being able to demonstrate patient benefit.

Okay. Great. Maybe in 30 seconds or less, sorry, Bryan, could you give us an overview of what FulcrumSeek is?

Yes. So very quickly, that is our discovery platform where we do our screening, focusing on genetically defined rare diseases in an unbiased way, looking to identify targets that modulate gene expression. I think what's most exciting about FulcrumSeek, we feel like it's very much been validated now by not only our 3 clinical programs but our 2 collaborations. We feel like this positions us very well to efficiently identify additional targets and programs that we hope to bring into the clinic in the near term.

Okay. Great. Thank you. With that, we are at the end of our session. So thanks, guys, for coming out to Vegas and participating with us. And thanks, everybody, for joining our session.

Thanks so much.

Thank you.

Thank you.