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

All right. Welcome, everyone, to this session of the Crédit Suisse Healthcare Conference. I'm Judah Frommer, Smid-cap Biotech Analyst here at Crédit Suisse. And we're very excited to have Bryan Stuart, CEO of Fulcrum Therapeutics with us. Bryan, maybe we'll just jump in with an intro to the company, specifically some background on the FulcrumSeek platform that I think investors forget kind of drives the discovery process here.

Yes, absolutely. And thanks, everyone, for joining us. So Fulcrum was started about 6 or 7 years ago, really around the idea of identifying targets to modulate gene expression in order to come up with disease-modifying therapies for genetically defined rare diseases. So the whole idea is start with genetically defined rare disease, known root cause and look for a target that were either up or downregulate gene expression and be able to come up with a drug that is really disease-modifying versus something that's more symptomatic. And I think what's maybe a little bit unique about our approach is that we are focused primarily on small molecule targets, which I think at the time was a little bit contrarian, but that discovery engine, as we started it has now led to multiple clinical programs and hopefully more INDs on the way.

Okay. Great. So moving into your sickle cell program, FTX-6058, fetal hemoglobin induction is a well-documented approach toward symptomatic improvement in sickle cell. Where does 6058 differ mechanistically versus other HbF induction approaches?

Yes. So as you mentioned, sickle cell disease is -- unfortunately, it's a terrible debilitating disease. It affects 100,000 people plus in the U.S., millions worldwide. What's very interesting about it is there is one known way to be able to treat all of the symptoms of the disease, and that's by inducing HbF. And we know this from human genetics. So there are people who have both sickle cell trait as well as a second mutation, which causes their fetal hemoglobin to be expressed. This is called hereditary persistence of fetal hemoglobin. And what we know is as fetal hemoglobin, HbF, is more highly expressed, it reduces or completely eliminates the symptoms of the disease. So the sickle cell space, the market has been looking for an HbF inducer for a very long period of time, literally for decades, particularly a small molecule, something that could be taken orally, something that would have broad applicability. That's exactly the approach that we took when we identified FTX-6058 about 5 years ago. And the approach, and we've now shown with our data earlier this year at EHA that we can successfully and robustly induce HbF, and that's really differentiating. So right now, in terms of oral HbF inducers, hydroxyurea is a standard of care that has very modest HbF induction and a lot of limitations in terms of safety and tolerability. And the rest of the approach is -- you'd asked about the competitive landscape, is primarily gene editing. So I think one of the reasons we were very excited about the initial data that we generated is we're showing that we are able to do what the field has been so interested in doing for a long time, which is once-daily oral pill that can induce HbF.

Okay. Got it. And mechanistically, with ED inhibition, any theoretical safety concerns with the mechanism? Can you touch on results from your tox studies, maybe? And we do get questions from the oncology space on this mechanism with the safety read through.

Yes. I think I can share where we are now. So we've -- from a tox perspective, we've completed our 3-month tox. Our chronic tox program is progressing. Our safety and tolerability data that we've generated so far has been encouraging. So we had our Phase I healthy volunteer data, where we dosed up to 60 milligrams. We -- essentially there were no safety issues of concern that emerged from that. We're in the middle of our Phase Ib trial right now, dosing up for -- up to 3 months in sickle cell patients. We shared initial data, as I mentioned earlier, at EHA. So far, the safety and tolerability data has been encouraging, but we also appreciate it's early, and we're actively in a trial. So we'll obviously continue to certainly focus on that.

Okay. Great. And maybe we could just give a quick overview of the Phase Ib design in patients. You did disclose that you'll add a 12-milligram cohort earlier today. So what was behind the decision to start at 6, go to 2 and then head to 12?

Yes. And maybe just to start with a little bit on our preclinical data set. So sickle cell disease and specifically HbF induction is just very interesting in that it's got high translatability from what you see preclinically in terms of the CD34 positive assay and the Townes mouse model to what has translated into the clinic in terms of HbF induction. So we saw -- we generated very robust preclinical data. We then went into healthy volunteers last year, and we saw robust increases in mRNA, but we weren't dosing long enough to be able to observe increases in protein. So we were very excited earlier this year when we shared our initial data, where, again, we saw HbF increasing in the 6-milligram dose. We saw it increasing into the levels of 5% to 10% increases, which is our ultimate therapeutic goal for the program. So that was very encouraging. But one of the things that didn't come out from our initial sickle data is we had not yet dosed any patients who are on background hydroxyurea. Despite all of hydroxyurea limitations, it's still the standard of care. So what we announced at that time is we would be moving forward with our 6-milligram cohort, our 2-milligram cohort in subjects that were both on HU as well as monotherapy. Both of those are progressing. And then we announced this morning that our third dose cohort will be at 12 milligrams. And again, we anticipate dosing both monotherapy and patients on HU. Some of the important things that we want to understand from all of the dose cohorts is certainly safety and tolerability, but we also want to understand one of the things that we observed in the healthy volunteer data is that we saw different levels of mRNA induction and essentially increases in mRNA induction the higher we dosed. So we want to see if those trends continue as we go to 12. And again, I think we feel like we're coming from a very exciting place in that at 6, we're already beginning to get into the levels that we think will be transformative for patients.

Okay. And when you talk about transformative levels, I think you've set the goalpost pretty clearly at this point for kind of 5% to 10% incremental HbF induction. You have, like you said, the gene editing approaches that are aiming for that 25%, 30% plus. Going with that 12-milligram cohort, is the idea to be maybe at the higher end of that 10% or to further explore if you can get outside of that range even?

Yes, it's a great question. And I think -- so one of the reasons and the reason our therapeutic goal is 5% to 10% is there's this very broad data, which is everything from human genetics data, from hereditary persistence of fetal hemoglobin that I mentioned, real-world evidence, literature reviews. Now you do have emerging gene editing data. And you see very consistently that once you get into that range of the 5% to 10% increase that you have essentially impact on all of the symptoms of the disease. So we were triangulating between that as well as what we're hearing from KOLs in the space, which is to come up with something not that will be clinically meaningful, but something that will be transformative for patients. And we get this very consistent triangulation that if you can achieve 5% to 10%, this is the potential to be standard of care. So as we think about a higher dose, certainly, we don't know if we can get above that 5% to 10% range. We feel like anything above that will obviously be -- will be great. That will be well received. We don't feel like it's necessary considering the impact we will have, but that's certainly something that we want to understand.

Okay. Got it. And you mentioned the EHA data a couple of times. So it seems like investor reaction from that data was probably more tied to compliance within a historically noncompliant patient population and concerns around that as opposed to necessarily the mRNA or HbF induction levels that we're seeing. So can you talk about the changes you've implemented in the trial to improve adherence and give us an update on how that's going with subjects that have enrolled since then?

Yes, absolutely. So at the EHA, we shared patient -- essentially 5 patients' worth of data. And as you mentioned, I think the encouraging element is that even though this was our initial dose cohort of 6 milligrams and even though we are only dosing for 3 months, we already saw 2 patients get to these 5% to 10% levels. That part was very encouraging. But we certainly did get a lot of questions in that we had 2 patients that were nonadherent. So one of the things that we've done that we've talked about, I think at EHA and since then is transitioning to observed dosing. Observed dosing is very commonly used in a lot of small molecule trials across different disease states. And we feel like, as we've implemented that, we feel like it's been effective and it should allow us in our next data set to really answer some of the questions that were coming out. And some of the questions that we got, and I'm sure that you got as well where if there is non-adherence, are there safety and tolerability issues? Are there potentially nonresponders? And when you shift towards observed dosing, will that positively impact the results you see in those subjects? So we look forward to being able to address that. I think one of the things that we can say is that out of those 2 subjects in the initial data set, one of them was still early enough in the trial that we transitioned them to observed dosing. So the impact of that will be in the next data set that we share.

Okay. Interesting. And maybe this is a good time to just get your general thoughts and maybe some of the work you did before initiating any clinical activity here on adherence in sickle cell, right? It would seem that a pill that's relatively easy to take every day could improve adherence. So what have you heard in your initial work around that? And then I guess the flip side of that is obviously, a much more rigorous and intensive procedure, but is there an argument to be made that in a noncompliant population, something like a gene therapy is the way to go because you're not sure people will take their meds anyway?

Yes, I would say, as we've looked at this and there were certainly learnings that came out from our side as we kicked off our trial. And as we shared at EHA, one of the learnings was certainly the benefits of observed dosing. And as I mentioned, observed dosing is actually not unique to sickle cell disease, it's broadly utilized across a number of diseases. And for a number of reasons, it's helpful, particularly in the clinical trial space because it just allows you to eliminate more variables and really get a more reliable data set. So we've implemented that, we believe, as I mentioned, that it's been effective. And that's something that we'll continue with in our Phase Ib trial. We also imagine continuing with it in our registrational trial. And again, we think that does work and will be effective. I think one of the reasons we've been so excited about 6058, and the field has been so excited about 6058 is sickle cell disease, unfortunately, is a terrible disease, morbidity, mortality. People living with sickle cell disease die a lot younger than they should, and it is a terrible disease, and it is a global disease. So we're still very enthusiastic. And I think the field is incredibly enthusiastic about a small molecule. I think a lot of the gene editing data that has emerged is very exciting. I think the challenge is obviously that it's a highly invasive procedure. And this is a patient community and a disease state where access really is as important as innovation. So we still believe a small molecule is absolutely the best approach. And I think we feel like we're executing our clinical trial in the best way to generate supportive data.

Okay. Great. And you touched on more patients in subsequent cohorts being on background HU. What would you expect the additive effect or synergistic effect of HU plus 6058 to be? And would you expect that, that might vary by dose level?

Yes. And maybe to address the first question. I think the question that we get and one of the initial questions that we got when we brought this program into the clinic is despite all the limitations that I just mentioned with hydroxyurea, about 30% of patients respond to it, efficacy is waning, safety and tolerability challenges. It still is a standard of care, and it's a standard of care because the disease burden is so great, and it's a therapy that has shown to be efficacious. So one of the initial questions that we got was will 6058 work on top of hydroxyurea. So hydroxyurea also induces HbF. It induces a relatively low level of HbF. And everything that we looked at preclinically has suggested that 6058 will be additive to HU. But as I mentioned in the data that we shared at EHA, none of those subjects were on background HU. So to answer your first question, one, we do anticipate that it will be additive. Obviously, we need to address that through clinical data. In terms of variability, that's not something that we have the answer to, but I think as we generate more data certainly, our goal is to be able to generate sufficient data in the Phase Ib trial that, as we've talked about, we would like to transition ideally into a registrational trial and we want to be able to answer that question. One, does it work on top of HU? And then two, how consistent is the response if it does?

Okay. And I think today, you updated some time lines around readouts for the Phase Ib. So can you give us that updated time line and how that could influence timing for initiation of a potentially registrational trial?

Yes. So one of the things that we did share this morning is that we anticipate enrollment will go into 2023. And I think as we mentioned, it's the 2-milligram dose, it's a 6-milligram dose, and it's now the 12-milligram dose that we just announced this morning. In terms of the registrational trial, Obviously, we need to engage with the FDA and come to -- and other regulators and come to alignment on a trial design. It's still our goal to initiate a registration trial next year in 2023.

Okay. Got it. And how well defined would you say or how open to conversation is an accelerated pathway within this indication? Is HbF induction in your mind a potential biomarker that could serve as the basis for approval?

Yes. So we do need to have those conversations with the FDA. I think one of the things that we've talked about in the past is HbF is extremely unique, in that it truly is predictive of patient benefit. And the data set that supports that, and I went through all of the pieces of data before, it's just very unique. It's been so well studied, and the impact of increases is so clear that we believe it certainly does predict benefit for patients. But ultimately, we need to have those conversations with the FDA and understand whether or not HbF would be appropriate.

Okay. That makes sense. And then just looking beyond sickle cell for this assay, is there a potential to revisit beta-thalassemia in the future? Would work from the Phase Ib and potential registrational trial, potentially add insight into dosing in beta-thal if you went in that direction?

Yes, absolutely. We certainly do feel that inducing HbF will obviously have benefits in beta-thal as well. I think one of the things that we did earlier this year is we made the decision to really focus our priorities and our investment in sickle cell disease, and as a result, deprioritize temporarily the beta-thal program. So that is something that we will revisit. I think the other benefit is the data that we're generating, both the dose-ranging data as well as the safety and tolerability data should hopefully put us in a position that we're able to move more quickly into beta-thal. But certainly, we see the utility with a small molecule HbF inducer in that disease.

Okay. Great. And then just switching gears to your lead asset, losmapimod in FSHD. Can you give us a brief introduction to losmapimod, the unmet need in FSHD and maybe also some highlights of ReDUX4 for a Phase II trial?

Yes. So maybe starting with the disease itself. FSHD is a terrible disease. It's the second most prevalent form of muscular dystrophy. And it's actually a very unique disease in that despite the fact that it's -- it is the second most prevalent form of muscular dystrophy, it is typically a lifelong disease. Patients get diagnosed usually when they're in their teens. And FSHD has a known root cause, and that's the aberrant expression of DUX4. So as DUX4 is expressed, it essentially kills muscle, fat infiltrates muscle, and it leads to a lifetime of disability. As I mentioned, what's particularly unique is even though it's so devastating, the root cause wasn't known until a little over a decade ago. And as a result, people didn't know how to study it. They didn't know how to identify target. So we use FulcrumSeek, our product engine. We made the unique relationship between p38 MAP kinase inhibition, lowering DUX4-driven gene expression. And that put us in a unique position in that we were then able to go in in-licensed chemical matter, and this is the drug losmapimod that we got from GSK, had been studied in over 3,500 subjects, primarily looking at inflammation, and it allowed us to transition right into a Phase II trial and do so with a drug that has a safety and tolerability database that was very appropriate for a lifelong disease. So I mention it had been dosed in over 3,500 subjects. You had an attractive safety and tolerability profile. It's an oral drug taken twice a day. And we were able to transition that into ReDUX4 and that was our Phase II trial. And really, we needed to answer the question, which the field had not been able to answer in FSHD, which is -- this is a disease of variable progression, that it had been studied in a relatively limited way in the clinic, so how can we find or can we find the right endpoint, the right duration of treatment, where we can show -- first of all, we can show decline within 48 weeks or a reasonable time period, and then we could see benefit. And that's exactly what we did. So in ReDUX4, it was 80 subjects. We studied them for 48 weeks. And originally, the intent was to be able to show via a biomarker, which is DUX4-driven gene expression taken via needle biopsy to show that DUX4-driven gene expression was decreasing. And then we had a number of secondary and exploratory endpoints, looking at fat infiltration, using whole-body MRI, looking at strength, looking at function, looking at patient-reported outcomes. And what ended up happening with the trial is that the DUX4-driven gene expression proved to be very difficult to measure in patients. And the reason for that is DUX4 is stochastic. So you're going back to a same spot for a needle biopsy, 48 weeks apart. And essentially, it proved to be very challenging. I think what the surprise was and what we were very encouraged by is that we recognize patient benefit across a number of secondary and exploratory end points. So we did show that losmapimod nearly stopped fat infiltration using whole body MRI. We saw patient benefit with strength. We saw patient benefit with function, particularly using something called reachable workspace, which is ultimately our primary endpoint in our Phase III trial, and there was benefit in patient-reported outcomes, and these were statistically significant benefit. So we were very encouraged by the fact that despite the challenges and the limited amount of clinical experience in FSHD, we could show that patients were declining within a 48-week time period, and we could show that losmapimod was having an impact within a 48-week time period. And that set us up in a wonderful position to go interact with regulators in the U.S. and Europe and gain alignment on a Phase III trial design.

Okay. Got it. And maybe it's by default, but I think you guys are kind of leading the charge on reachable workspace as an endpoint, just given how advanced in the clinic you are within this indication. So in conversations with regulators, KOLs, the community and patients, how is reachable workspace kind of resonating as a potential primary end point for the Phase III?

Yes. So one of the things that we did at Fulcrum and even prior to the Phase II trial is actually we spent a lot of time with clinicians, with patients, with their families and really tried to understand what was important to them. And there were a few things that really came out of that. One is that they -- while ultimately everybody is looking for something to stop progression of the disease, really appreciated the opportunity to have a drug that would slow progression of the disease. And secondly, what's interesting about FSHD is that we consistently heard that upper body mobility was as important as lower body mobility. And maybe one of the reasons for that is that with FSHD, it typically starts in the upper body and then progresses down throughout the body. In over 97% of patients, their shoulders are affected and their ability to move their arms above their shoulders. So reachable workspace has really resonated with the community, with patients. And I think one of the reasons why it resonated with regulators is that it is highly correlated with activities of daily living. So it makes sense, somebody's ability to comb their hair, to brush their teeth, to feed themselves. And this is really one of the things that people who live with FSHD -- is just so difficult for them is this loss of independence. So those -- the correlated nature with activities of daily living, I think that's the part that has really resonated. And I think regulators came to alignment about the Phase III study design.

And how well designed would you say is, I guess, that minimally necessary change in reachable workspace? Or are you still kind of proving that out as you go forward with development here?

Yes. I think one of the things in the Phase II trial is that, again, we were excited about the fact that we did separate in reachable workspace from placebo. One of the other elements that has come out since then is a couple of weeks ago at World Muscle, we shared 96-week data. And what we were very encouraged by -- and this is the ReDUX4 trial, the open-label extension, is that subject in the trial who were on losmapimod and then continued on losmapimod for an additional 48 weeks to get to 96 weeks, they saw this durability of effect. So essentially, the benefit from reachable workspace was still there. So that part was very encouraging. The correlation with activities of daily living, I think, is well established. And at the same time, we continue to do more work to really establish that measure of clinical benefit. But I think we feel like the data that we've generated so far has been very encouraging and very supportive as we continue to go down the path of the trial.

Okay. Got it. And you've mentioned that your current focus for losmapimod obviously, is on FSHD, but at the same time, I think you guys have talked about thinking about other genetically defined diseases within the muscular dystrophy spaces and other opportunities to utilize FulcrumSeek. So are there any other disease areas or targets that you could possibly pursue? And maybe what are ongoing FulcrumSeek investigation areas currently?

Yes. So for losmapimod, our focus really is on FSHD. And that's where our resources and investment is going. One of the things that has come out of the ReDUX4 trial is I think we've really shown an ability to not only from the discovery perspective to identify a target that's potentially disease modifying in a form of muscular dystrophy, but also to develop and utilize the right clinical tools to be able to show that benefit. So as we think about what's next for Fulcrum and the next programs to hopefully enter the clinic, broadly, the muscular dystrophy space is certainly one that's very interesting to us. And I think we continue to build up expertise both from a biology perspective, from a drug discovery perspective, but also from a translation perspective and a clinical development perspective.

Okay. Got it. And I think given the work that you guys have done within the FSHD space, there are some alternative modalities kind of coming down the clinical development pathway specifically with RNA-based approaches. How do you think about competition? Is competition good within this space where there is a lot of unmet need? And then how do you think about route of administration within this indication as well?

Yes. It's a great question. And yes, we absolutely think competition is positive within the space. As we think about FSHD, how debilitating it is, how many people unfortunately suffer from it globally. You think about other forms of muscular dystrophy, there has been far too little innovation and investment in the space. But I think it's always very encouraging to have more companies coming into the space and trying to develop programs. And while we're very excited about losmapimod and the potential of it to be standard of care, there should be other therapeutic alternatives available as well. I think one of the things that we're excited about with losmapimod is not only have we been able to demonstrate efficacy already, is having a lot of safety and tolerability data, the ability, in our case, to be able to manufacture at scale. All of these things, I think, puts us in a very advantageous position. So other programs are certainly coming into the space. That's exciting for patients, but we feel like with what we've been able to demonstrate already that we're in a great position as we look to execute on the registrational trial.

Okay. Great. And then maybe just to wrap up, I think it was yesterday, you made an exciting announcement about rounding out the executive team at Fulcrum with a new CMO and CSO expected to start very soon. So can you just give us a minute on their backgrounds on how they fit within the broader organization?

Sure, absolutely. And yes, we are very excited about both Santiago and Jeff. So Santiago Arroyo joined us as our Chief Medical Officer starting yesterday, tremendous experience in drug development, building teams, leading teams, bringing rare disease drugs through the FDA. He was most recently the CMO of Momenta, which was obviously acquired by J&J. Before that, a significant experience at a number of successful pharmaceutical companies. So as we think about being in a position now with hopefully, having 2 registrational trials in the clinic next year, Santiago's background is a great fit for us. Jeff Jacobs also joined as our Chief Scientific Officer. He has a wonderful experience in drug discovery, so wonderful experience in helping to support and advance drugs into the clinic. So we couldn't be more pleased. These are very exciting announcements for us to make and to be able to attract 2 people of the caliber of Santiago and Jeff to look at the company and want to get involved is great news for us, and we're excited to work with them.

Okay. Congrats on those hires. And I think we'll wrap it up there. Thank you for the time in participating.

Excellent. Thank you, Judah. Appreciate it.