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

All right. Thank you for joining us. It's my pleasure to be here with Bryan Stuart, President and CEO of Fulcrum. So Bryan, great to have you, and please go ahead.

Wonderful. And thank you for the opportunity, and thank everybody for joining us here today. So today, we'll be making some forward-looking statements about the company, and you'll see here on Slide 3. So at Fulcrum, we're really focused on regulating gene expression to treat the root cause of genetically defined rare disease. And we've built our organization and our approach, really taking advantage of some of the very meaningful advances that have taken place in terms of disease understanding over the last number of decades. So there's been a great advancement in terms of understanding gene regulation and understanding the genetic root causes of hundreds or thousands of rare diseases. And we've built up at Fulcrum, a product engine, as you see on Slide 4, where we look to very efficiently and reproducibly identify targets that can modulate gene expression and turn a disease profile into a healthy cell profile. And how we do that, on Slide 5, is with this patient-centric product engine that we've built. So everything we do starts with the patient where we're using patient-derived samples or differentiated cells. We do sell modeling in which we then interrogate the disease with our proprietary CRISPR library or our small molecule probe library. And then we're able to utilize both machine learning and computational biology to analyze that data and identify targets and identify pathways that have the potential to modulate gene expression, treat these diseases at their root cause, and do so in a way that doesn't negatively impact cell health. We're then focused on transitioning programs into the clinic and coming up with appropriate biomarkers to allow us to move as efficiently and effectively as possible through the clinic and, hopefully, to market. On the next slide, on Slide 6, we have a couple of illustrative examples of the product engine. And these are 2 clinical programs that we'll talk more about today. On the left is a program losmapimod for FSHD, facioscapulohumeral muscular dystrophy, which is the second most prevalent form of muscular dystrophy, but one that lacks any therapeutic alternatives, either approved programs, off-label products or any other drugs in the clinic today. And we identified uniquely a target with our product engine. We were able to then in-license chemical matter that existed, and moved very quickly from identifying a target to entering a Phase II trial in less than 2 years. And on the right side of the slide is another example, and this is one where we utilized our own medicinal chemistry. So we identified a target 60-58, which induces fetal hemoglobin for people living with sickle cell disease or beta-thalassemia. And we went from target identification to entering the clinic in less than 3 years. Part of the strength of our product engine is the ability to ultimately identify the best source of chemical matter and be able to advance to patients as quickly and efficiently as possible. On the next slide, Slide 7, it really shows the novel advancement that we've made of late, which is scale. So these 2 programs that I referenced before came out of our original version of the product engine, where we were doing single disease screens, and we were interrogating individual diseases at each time. From those screens, we were able to derive 3,000 to 4,000 data points and have been successful in identifying multiple targets. But what we've been able to do is really build up our product engine, FulcrumSeek as we call it, to now be able to do far more robust screens, taking advantage of high-content imaging, taking advantage of machine learning. So now we can derive literally tens of millions of data points from each screen, and it really gives us tremendous potential as we think about fulcrum and the ability to treat genetically defined rare diseases at a scale that we've never seen before. In terms of our pipeline to date, as we mentioned, losmapimod in a Phase IIb study, which we intend to read out later on this quarter in June at the FSHD IRC, FTX-6058, which is an EED inhibitor, which we'll speak more about, is currently in a Phase I healthy volunteer study. And we intend to have -- be able to share data from that study midyear. We also have a number of preclinical programs in the muscle, CNS and hematology space. And additionally, some of the power of the product engine is we believe it's applicable towards many different genetically defined rare diseases across different disease states and therapeutic areas. So while we look to advance programs internally, we'll also look to utilize collaborations to find partners who can advance programs in alternative areas. And in the last 18 months, we've executed 2 of these collaborations, one with Acceleron around a genetically defined pulmonary disease; and one with MyoKardia around genetically defined cardiomyopathies. So now on Slide 10, we'll talk a little bit more about losmapimod for FSHD. So as I mentioned, FSHD is the second most prevalent form of muscular dystrophy, approximately 16,000 to 38,000 people living with it in the United States, and about 0.5 million worldwide. And unlike other muscular dystrophies, there, unfortunately, has been relatively limited clinical programs and investment. With no programs approved and nothing else even in the clinic right now. So our -- the disease, the way it manifests is fat infiltrates muscle. And patients are typically diagnosed in their late teens or early 20s. It is a familial disease. So 2/3 of the cases are familial. So patient identification becomes easier. And essentially, patients will then continue to decline throughout their later teens and 20s, many of them ultimately ending up in a wheelchair. So the disease typically manifests initially in the face, then goes down through the body via the shoulders. And patients have loss of mobility, loss of independence as muscle continues to be destroyed by fat. Patients report pain, anxiety, depression, and has a very meaningful impact on their lives and the lives of their families. On Slide 11, we were very enthused that the FDA did a patient-focused drug development day last year with the FSHD community. So they were able to hear directly from patients, from family members about the impact the disease has on them and their desire to just find a potential therapy that can slow the progression of the disease. What makes FSHD, a good fit for Fulcrum's product engine is it's a genetically defined disease. There's a known root cause and tremendous unmet need. So about a decade ago, DUX4 and a barren expression of DUX4 was found to be the cause of FSHD. Also through additional clinical work, we learned that DUX4 doesn't need to be turned off. Even just turning it down has a potential to have a meaningful impact on the disease. And with that in mind, we then put FSHD into the Fulcrum product engine. We do our screens in an unbiased way. So we looked at a number of patient-derived myotubes. And we had no hypothesis going in, but rather, we let the science take us towards a potential treatment. And we uniquely identified the p38 map kinase inhibitor down-regulates DUX4-driven gene expression. You see here on the left, a reduction in both DUX4 as well as a downstream gene in the gray. These are clinically achievable concentrations. In the middle, a reduction in apoptosis. And on the right side of this slide, it was independently verified by another investigator named Fran Sverdrup, who made the correlation between p38 and DUX4 after Fulcrum did. And obviously, we're very enthusiastic to see that connection made by Fran as well. One of the very unique attributes about this is we were then able to look across the landscape. There had been a number of p38s that had been in the clinic, primarily for inflammatory diseases. The vast majority of them had relatively few human exposures, and some of the earlier versions of p38 have off-target side effects. But there was one, losmapimod, that had been successfully dosed in over 3,500 subjects. It had a very attractive safety and tolerability profile, and we thought that was extremely important for a chronic disease. So we were able to in-license that from GSK and then begin a very integrated clinical development strategy, which we lay out on Slide 14. So the first thing that we did was to work with patients, work with clinicians, work with investigators to identify suitable endpoints for the trial. We are one of the first companies ever to seek to develop a drug in FSHD. And we wanted to identify endpoints that were both representative of disease progression, and equally importantly, had the potential to show a decline within a period of time that would be appropriate for a trial. We then went into a Phase I study, where we confirmed that losmapimod penetrates the muscle of FSHD patients, and we also confirm target engagement. And then we have 3 ongoing trials. So one is a natural history study, working with the NIH and tracking hundreds of patients over multiple years to really understand disease progression independent of therapeutic intervention. And then we have 2 ongoing trials with losmapimod. One is an open-label trial at a single site in Europe. And this, we call a learning study. It's a 52-week study. And really helped inform some of our thinking around ReDUX4. And ReDUX4 is a placebo-controlled trial, for which I mentioned, we'll be reading that out late in the second quarter. And on Slide 15, we have more color on ReDUX4 itself. So we enrolled approximately 80 patients. It's a randomized, double-blind, placebo-controlled style international. Originally, the trial was scheduled to be 24 weeks. And in the course of the trial, COVID hit, and there were a number of sites that had the potential to close and patients had the potential to miss visits. So at that time, for those patients who hadn't yet completed, we extended the trial to 48 weeks. So that allowed us to keep the trial, and it also allowed us -- gave us the benefit of allowing patients to stay -- those on the drug arm to stay on losmapimod for a longer period of time, which we think has the potential to be beneficial in a disease that has variable progression. The primary endpoint of ReDUX4 is a reduction in DUX4-driven gene expression via a needle biopsy. So essentially, we are able to use an MRI to guide us to a muscle in the leg. The MRI can help ensure that the muscle in the leg will have DUX4-driven gene expression, do a needle biopsy, and then a return biopsy at either 16 or 36 weeks at the same site. We also have a number of very relevant secondary and exploratory endpoints. One of the secondary endpoints is whole body MRI. We recently presented on this at the MDA conference. Whole body MRI has the potential to be an extremely important tool in neuromuscular drug development because it can measure and pick up changes that are relatively modest in shorter periods of time. And also what we showed at the MDA conference is that whole body MRI is highly correlated with functional endpoints. In terms of some of the exploratory endpoints, we utilize things like Reachable Workspace. Reachable Workspace is essentially, we utilize a Microsoft Connect camera system. Patients will look to then move their arms, and that is tracked. One of the reasons why it's such a relevant endpoint is it is one of the very key complaints from patients. Because of the progression of the disease, this loss of mobility, loss of ability to move their arms above their shoulders has very meaningful impact and high correlations with activities of daily living. Additionally, we have things like timed up and go, and FSHD timed up and go, which measures a patient's ability to get up from a chair or table and walk. Things like dynamometry, muscle strength, and also patient-reported outcomes. And the totality of this data will be read out at the FSHD IRC. On the next slide, Slide 16, we show an interim analysis that we did on the first 29 patients. So in this interim analysis, we only looked at the primary endpoint. We didn't look at any of the secondary or exploratories. And what we learned and some of this are learning from our open-label study, is that while an MRI can guide us to a muscle in the leg where DUX4-driven gene expression is being expressed, it is highly variable. So we looked to do a prespecified sensitivity analysis, including in the interim analysis, where we observed a large reduction in losmapimod for those biopsies, which were in the highest quartile relative to placebo. And on the randomized basis, it looked relatively similar. So we were focused and will continue to do prespecified sensitivity analysis in the full data set. And we don't believe that this limits the potential utility of losmapimod. So we believe, and investigators believe that as the disease progresses, all patients will have both high and low expressing muscles. So while there is a sampling bias and a limitation with some of the needle biopsies, we believe losmapimod has the potential to show benefit in all patients with FSHD. And this is a summary of the data that will be read out here at the FSHD IRC on Slide 17. Consistent with our hypothesis, that reducing DUX4-driven gene expression can reduce fat infiltration and show a benefit versus placebo in clinical outcome assessments and patient-reported outcomes. We'll have a number of both novel, modified and established endpoints. And from our perspective, we would be highly encouraged if we were able to recapitulate the data from the interim analysis, where we were able to observe any trends of patient benefit across the secondary exploratory endpoints, which would really be unprecedented in this devastating disease. We'll next move on to our second program, which is FTX-6058. On Slide 19, you'll see FTX-6058 is for select hemoglobinopathies. And so starting with sickle cell disease, sickle cell disease is a global and devastating disease: 100,000 patients approximately in the United States, 50,000 in Europe and millions more worldwide. And sickle cell disease leads to shortened lifespan, pulmonary hypertension, stroke, to coronary syndrome, ulcers and pain, devastating impact on patients. And what's known about sickle cell disease is there is a very clear and validated approach to treat it, and that is by inducing fetal hemoglobin. So as you see here on the right, we know this from human genetics. So there are people who have both the sickle cell trait, but they have reduced or eliminated symptoms due to another genetic mutation called hereditary persistence of fetal hemoglobin. And these are people who also have their fetal hemoglobin expressed, and it is clearly shown to reduce and/or eliminate the symptoms of the disease. So as you see here on the bar, as you -- as more fetal hemoglobin is expressed, it continues to have a greater benefit until when people have about 20% to 30% fetal hemoglobin expression, at that point, they can be asymptomatic. So with that knowledge in mind, we then looked at sickle cell disease and beta-thalassemia within the Fulcrum product engine with our approach. And really, what the industry is looking for is a small molecule that has the potential to induce fetal hemoglobin and that has the potential to be transformative for people living with the disease. On Slide 21, what we were able to identify is through our screen, both our CRISPR and our compound screen, is that we identified both known mechanisms, which helped validate our approach, but also that EED inhibition induces fetal hemoglobin. We then use our own medicinal chemistry, and we created a compound with excellent drug-like properties, highly selective, a clean off-target profile, which we were able to quickly advance into the clinic. On Slide 22, we then did -- we looked at our mechanism in vitro versus other mechanisms that are known to induce fetal hemoglobin. And essentially, with the treatment for sickle cell disease or beta-thalassemia, you're looking to do 2 things: One, most importantly is to induce fetal hemoglobin; and two is to do so in a pan-cellular way. So F cells are cells that produce fetal hemoglobin. And in order to essentially phenocopy hereditary persistence of fetal hemoglobin, you need to achieve both, but you need to have a large number of cells expressing fetal hemoglobin rather than a small number of cells expressing a lot of fetal hemoglobin. And that's exactly what we saw. As you see here relative to other mechanisms, saw a larger increase in fetal hemoglobin expression. We saw that in a pan cellular way with a very attractive F-cell profile. We then looked at the CD34 cell system, and we looked at both patients and healthy volunteer-derived cells, and we saw a very attractive and robust increase in fetal hemoglobin ranging from 8% to 18%. We know, and as you can see from the chart on the right, even relatively small increases can have a meaningful benefit for patients. But as we get towards these 8% to 18% increase levels, it has the potential to have a very meaningful impact. In addition to CD34, we looked at the sickle cell Townes model. And what you see here is we demonstrated robust target engagement. In the middle panel, we did that with an increase in F-cells, larger than what we observed with hydroxyurea or with a competitive mechanism. And we saw a meaningful fetal hemoglobin induction as well. And on Slide 25, we also saw very positive impacts on the hematological parameters of the disease, including increases in total hemoglobin, red blood cells and F-cells, and reduction in white blood cells and reticulocytes, also a reduction in spleen weight. And increased spleen weight is a common manifestation of sickle cell disease as blood pools up within the spleen. So very encouraging results from the Townes mouse trial. And what we've been extremely enthusiastic about is both the robust increases we've seen and the consistency of the increases that we've seen. So whether across HUDEP2 cells, healthy CD34s and CD34s from sickle cell patients, a wild-type mouse or a Townes mouse, we've seen this very consistent increase in fetal hemoglobin. And we believe that this can then have an impact on patients all across the spectrum, independent of their starting fetal hemoglobin levels. We're currently in a Phase I healthy volunteer study right now. We announced recently at the ACS conference that we had begun the MAD cohort from the trial. And based on the modeling we've done, we anticipate a dose of between 6 and 20 milligrams is likely to be our anticipated dose moving forward. From a clinical and regulatory perspective, while we're in healthy volunteers right now, our goal is to treat people living with sickle cell by the end of this year. So that's a very active focus of the organization. And from the regulatory perspective, while there have certainly been some advancements in the space, the unmet need remains very meaningful. And we believe in fetal hemoglobin induction, the benefits are so well understood that it represents an excellent surrogate as we continue to move through clinical development. And from the commercial landscape, why we think 6058 has the potential to truly be a transformative therapy and one that can be the cornerstone of treatment, because it has the ability to address both presentations of the disease, both anemia and VOC-driven presentations. So today, hydroxyurea is the standard of care. Hydroxyurea has many limitations, from very modest and highly variable efficacy to significant tolerability issues, which cause a lot of patients to go off drug. So 6058 has the potential to be first-line therapy utilized at the very beginning of treatment if we're able to see this translation into the clinic. There are a number of other approaches in this space, and they're focused on either anemia-driven disease or VOC-driven disease. And again, we believe 6058 and inducing fetal hemoglobin has the ability to benefit both presentations. There's also a significant amount of work going on in cell and gene therapy. And while we think those are very interesting approaches, based on the size of the patient population, we think those will be -- and the challenges, a very complicated and risky pretreatment regimens, we think those will be reserved to the most severe patients, particularly if there's a small molecule available, which can induce fetal hemoglobin. Additionally, we're also very focused on beta-thalassemia, where inducing fetal hemoglobin has the same potential benefit. As I mentioned earlier, while we're very focused on the muscle and hematology, we believe that this approach, which has led to these 2 programs to date in the Fulcrum product engine, can be applicable towards many genetically defined rare diseases across a number of therapeutic areas. So these are the 2 collaborations that I mentioned, very excited to be in collaboration with both Acceleron and MyoKardia. And as we continue to advance the business, we'll look to bring forward more programs internally. We think there's a tremendous opportunity to partner with other outstanding biotech and pharma companies and advance even more programs. So we're extremely enthusiastic about 2021 and what the future holds for Fulcrum. So just to review some of the key upcoming milestones, Phase IIb data from ReDUX4 will be presented at the IRC conference, June 24th and 25th. 6058 is in healthy volunteers right now, and we anticipate being able to share data mid-year. We continue to advance our product engine, FulcrumSeek, with the meaningful advances that I spoke about in terms of scale and productivity as we look to move more programs that can treat the root cause of genetically defined rare diseases into the clinic. And we'll also look to advance our collaborations. As of the end of the first quarter, we had approximately $143 million in cash, and that provides runway into the fourth quarter of 2022. Thank you very much for your time.

Yes. Bryan, thank you so much for sharing Fulcrum's story, and we definitely look forward to updates later this year. Thank you very much.

Wonderful. I appreciate it.