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

Thank you for joining us today for Fulcrum Therapeutics KOL event on FSHD, a severe progressive and debilitating muscular dystrophy. I'm Naomi Aoki, Fulcrum's Senior Vice President of Corporate Communications and Investor Relations. Before we get started, please be reminded that we may make forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our future expectations and plans, clinical development milestones and financial projections. While these forward-looking statements represent our views as of today, they should not be relied upon as representing our views in the future. We may update these statements in the future, but we are not taking on the obligation to do so. Please refer to our most recent filings with the Securities and Exchange Commission for a discussion of risks, uncertainties associated with our business. With me on today's call are 2 key opinion leaders, Dr. Nick Johnson and Dr. Jay Han as well as Bryan Stuart, our President and Chief Executive Officer; Dr. Judy Dunn, our President of R&D; and Mel Hayes, our Chief Commercial Officer. Following their presentations, there will be a question-and-answer session. [Operator Instructions] Chris Morabito, our Chief Medical Officer; and Esther Rajavelu, our Chief Financial Officer, will also be on for Q&A. With that, it's my pleasure to turn the event over to Bryan.

Thank you, Naomi, and thanks, everybody, for joining us today. We're thrilled to be in a position to be able to talk to you more about FSHD, be joined by 2 distinguished key opinion leaders in this space and also talk more about our Phase III REACH trial, which is upcoming. So just to walk you through this morning session. I'll start with some opening remarks and a very brief corporate overview. I'll then turn it over to Dr. Nick Johnson, who will provide more background on FSHD and the unmet need. And by way of background, Dr. John is an associate professor of neurology and human and molecular genetics. He's the Vice Chair of Research and Neurology at Virginia Commonwealth University with a focus on inherited neuromuscular disorders. He has over 10 years of experience in muscular dystrophy trials. He's also a member of the FSHD clinical trial's research network and also the lead of the biomarker working group. We'll then turn it over to Judy Dunn, who is Fulcrum's President of R&D to talk more about both our ReDUX4 trial as well as our upcoming Phase III REACH trial, which is based on some of the key findings from that trial. Judy has got an extensive background in both drug discovery and development, has led multiple drugs through the clinic to approval, including in the rare disease space. We'll then turn it over to Dr. Jay Han. And Dr. Han is a Professor and Vice Chair in the Department of Physical Medicine and Rehabilitation at UC Irvine. He's a board-certified neuromuscular specialist. He's more than 20 years of experience taking care of patients with neuromuscular disorders, including FSHD. And most importantly, Dr. Han is also the principal investigator and developer of the reachable workspace tool, which we'll talk more about in the context of our Phase III REACH trial. And next, we'll then wrap it up by turning it over to Mel Hayes, Fulcrum's Chief Commercial Officer, who will talk more about the significant unmet need and very meaningful commercial opportunity that exists. So next, I'll focus on some of the key takeaways that we'll share with you today. So first and foremost, losmapimod is positioned to be a first-to-market therapy for FSHD. We've made tremendous progress. We'll talk more about some of the key learnings that came out of our Phase IIb trial, which we believe positions us extremely well for the REACH trial that we'll be starting in the second quarter of this year. And that progress is extremely exciting as we are potentially very close to finally bring in a therapy for this underserved patient population. We'll also focus on the unmet need that exists with FSHD. So as you'll hear more about today, FSHD is a severe, progressive and debilitating disease. People with FSHD are typically born healthy without symptoms. And then usually, in the second decade of life, they begin to develop symptoms, fat infiltrates their muscle. It has impact on function, impact on independence, many of them often ending up in a wheelchair, and unfortunately, no therapeutic interventions or nothing that they can do today to be able to slow or stop that. You'll also take away that this is a very large and addressable patient population. This is typically passed on from family member to family member, over 70% of the cases are people see their family members, their aunts, their uncles, their parents with this disease. And as a result, they're aware that they have FSHD, but are really looking for any type of treatment or therapy that can help them. And as I mentioned, unfortunately, there are nothing for people living with FSHD today. Not only is there nothing approved, there's also nothing else in the clinic. And as Mel will talk about from a commercial perspective, this is actually the second most prevalent form of muscular dystrophy. There are 16,000 to 38,000 patients in the U.S. alone, approximately 0.5 million patients worldwide and a tremendously well organized and very vested patient population looking for a potential therapy to come to market. We'll also take away from today that our Phase III REACH trial is really optimally designed to demonstrate efficacy. So some of the learnings from our Phase IIb trial, our ReDUX4 trial showed the benefits of losmapimod across a number of measures. So while DUX4-driven gene expression itself proved to be very difficult to measure due to the stochastic nature of it. We did observe in the course of a 48-week trial with only 80 subjects that the downstream benefits of reducing DUX4-driven gene expression were all apparent, in that, we were able to show statistically significant and clinically meaningful benefits in muscle health as measured by whole body MRI in strength, in function and patient-reported outcomes. And we're able to leverage those learnings into our Phase III REACH trial, which has reachable workspace as our primary endpoint and reachable workspace is a quantitative and reliable measure of function and disease progression. Dr. Han will be able to talk more about that tool. And Dr. Dunn will talk more about the findings from our Phase IIb trial. What's also important about reachable workspace is that it is highly correlated with activities of daily living, and independence, and we're very pleased that we had our regulatory interactions with both the FDA and ex U.S. regulators, and we're able to gain alignment on utilizing reachable workspace as our primary end point in our REACH trial. And then finally, Mel will talk more about the significant commercial opportunity that exists based on the severity of this disease and the significant unmet need. Next slide, please. So I'll give just a brief corporate overview of Fulcrum. So at Fulcrum, we aim to deliver disease-modifying therapies for people living with rare genetic diseases. And how we do that is using our FulcrumSeek product engine. So we take advantage of the fact that there are now over 4,000 rare diseases that have known genetic causes. And we've set up our discovery approach so we can screen at scale and very efficiently identify targets that modulate gene expression and allow us to quickly move into and through the clinic with potentially disease-modifying drugs. We'll focus more on FSHD today, but another example of our approach is our other program, FTX-6058, for both sickle-cell disease and non-sickle cell hemoglobinopathies. And this is an example of where we put FulcrumSeek against this other disease, sickle cell disease and where we know that the only way to treat all of the symptoms of the disease is by inducing HbF. We uniquely identified a small molecule that induces HbF. We have that now in a Phase Ib study, which we'll be reporting out later on this year. we believe there's a lot of applicability to our approach across genetically defined rare diseases in many therapeutic areas. And on the next slide, we'll show beyond the clinical programs, we also have a robust preclinical pipeline. And we have 2 active collaborations, 1 around genetically defined pulmonary disease; a second around genetically defined cardiomyopathies. Those are with Merck and BMS, respectively. And as we continue to advance our product engine and our capabilities and our ability to identify disease-modifying therapies, we believe there's a lot more potential to move more programs forward internally ourselves and do more collaborations in areas outside of our areas of focus. And then finally, we believe that with the clinical programs that we have as well as our discovery approach, as you see here on the next slide, it positions us extremely well for what we anticipate to be a very exciting 2022. Three potentially disease-modifying clinical stage programs, multiple clinical milestones. We're guiding towards our next IND coming out of our product engine in the first quarter of 2023. And we have a cash balance, which takes us into 2024, putting us in a very strong position. And with that, it's my privilege to turn it over to Dr. Johnson to talk more about FSHD.

Great. Thanks for the introduction. It's nice to see everybody virtually and talk about FSHD as an important condition with a high unmet need. Next slide, please. My disclosures. We'll go to the next slide. So FSHD is a rare genetic disorder where skeletal muscle is replaced by fat. And it's -- the primary pathophysiology is hypomethylation that leads to aberrant expression of the DUX4 gene. It is autosomal dominant. The onset and severity vary widely. So most people do develop symptoms as teens or young adults, but there's a whole range of symptom onset from infantile to even non-manifesting carriers. And one of the interesting things about FSHD is that it does have variable progression with periods of progression and plateaus. And you can see the picture graph there representing the really characteristic muscles that are affected by FSHD. It's in the name, so it's the face, the scapular region, the humeral region but then, in addition, the trunk and the distal legs as well. Next slide. There are, in fact, at least 2 different kinds of FSHD, type 1 and type 2. They are clinically the same. They're both caused by an aberrant expression of DUX4. The underlying genetics as to whether or not it's a truncation of the D4Z4 [ repetive ] element or if it was a mutation in that hypomethylation gene SMCHD, just gives you 2 different pathways to get to the same place. FSHD 1 represent, by and large, the majority of the cases, over 95% of individuals. In FSHD, the remainder. And this graph -- these graphs from Dr. [ Sinconi's ] work demonstrate that looking at an age corrective clinical severity score or the regular clinical severity score or a measure of manual muscle testing. You can see that across the board, individuals with FSHD 1 and FSHD 2 behave remarkably dissimilar. And in fact, in clinic, I can't tell the difference between FSHD 1 and 2, it's at the results of that underlying genetics. Next slide. And that, that clinical presentation in clinic is both characteristic and heterogeneous. So you can see these pictures here, highlighting many of the typical features that you see in individuals FSHD often really apparent even from the exam room door. And you can see, for example, in the upper left-hand corner, the transfer smile that comes with the facial weakness, and then a number of pictures demonstrating the severe scapular weakness that occurs with FSHD. The progression is typically stepwise involving the face first. the scapular muscles next and then some humeral and dystrophy so on and so forth. But you can see there with that scapular weakness, the inability to extend the arms over the head or forward and the amount of extra work somebody is trying to do just to even lift those arms to 90 degrees. So that scapular weakness is a big deal and really apparently you see patients in clinic. Next slide. And we did survey patients with FSHD using the National Registry of FSHD and myotonic dystrophy patients and family members. And so this is a cross-sectional survey of 328 participants with FSHD. And you can see the symptomatic themes represented there as well as the population impact score. And you can see that over 95% of patients reported problems with shoulders or arms as the highest disease burden. This makes sense. It's, again, beyond the facial weakness. It's the next area where people develop weakness typically. And so it's with them for the majority of the [ tree's ] course, again, beyond the facial weakness. And then when you look at how it affects our lives, so it's not only is it prevalent, but it is impactful, that population impact score is an aggregate measure of the mean LICA response by the frequency of the response. And so the higher the population impacts score, the more meaningful, that particular symptom, meaningful the impact with that particular symptom. And you can see problems for shoulders arms, again, top of the list with mobility and walking right behind it. Next slide. So more than what you can represent in a survey from my experience working with patients with FSHD. There are a number of different areas where people -- it really does affect day-to-day life. It's a progressive disorder, and it's just at least an incredible amount of disability. So inability to communicate via facial expression. I've had kids, teenagers who say that they get made fun of by their classmates because like, why are you angry with me, but I'm not angry with you. I just can't smile, the inability to do activities requiring any of the upper arms of brushing hair, putting dishes on shelves, et cetera. That truncal weakness as it develops can cause a number of different problems like even getting out of bed. And then, of course, with the problems with the legs as well, so trouble with tripping and falling, difficulty walking unassisted and people may require either canes, braces, wheelchairs, et cetera. And then with any other chronic disorder without available treatment, patients have lots of anxiety and depression related to that as well as fatigue. And we'll talk about pain in a second. Next slide. So these are the common co-morbidities as opposed to any other form of muscular dystrophy. Pain in myotonic dystrophy and FSHD is a huge deal. It's reported by 75% of patients in the back, legs, shoulders and neck. People often take non-steroidal anti-inflammatories or even opioids to deal with the pain that's associated with the condition. And fatigue is also commonly seen in individuals with severe mutations leading to earlier age of onset of FSHD, there can be a retinal vasculopathy in a coat syndrome that develops. And then it's pretty common that people have high frequency hearing loss. Some may require a hearing aid although that is pretty infrequent. And then respiratory failure may develop in approximately 20% or so of patients typically due to that restrictive truncal weakness. Next slide. It's a family disease because it affects somebody's ability to maintain independence. So there is a lack of or loss of physical independence, a reliance on family and other caregivers. And more than that, this is an autosomal dominant condition. So there's often guilts in families because it's a condition that's passed every generation down. So it really does have a pervasive effect across family members. And then beyond that, there's a financial burden as the disease progresses. So cost of supportive care, loss of financial opportunity or inability to work and then, of course, disruptive to an overall family quality of life. Next slide. So it is exceptionally readily diagnosable. I hope that you could see from the pictures that it's a recognizable condition. There's nothing else that looks like FSHD when you see clinic and you know what you're looking for. So oftentimes because there's not a disease-modifying therapy and there is a cost associated with genetic testing. We'll often do a blood test for the -- no mutation in just 1 family member and diagnose the remainder family members with -- based on clinical features and family history. But that blood test is typically done first for that D4Z4 repetitive element, the contraction that you see in FSHD type 1, but then you can also test for the SMCHD1 mutations with next-generation sequencing tests or as a last step, you can do a methylation assay. But all of these assays are commercially available. They're well recognized, and they have very high sensitivity and specificity. Next slide. So as I mentioned before, there are no approved therapies for FSHD. This is a big deal. I talk to patients all the time. That's when they come to clinic, it's one of the first questions people ask when something better is going to come out, what else is on the horizon? So there have been to date, no therapies have been shown disease modification or clinical benefits. Our prior studies have included albuterol, corticosteroids, biostat inhibitors and even supplement use. As I mentioned before, you treat the pain with standard therapies like ibuprofen or naproxen, even massage in some instances. We do try to avoid opioids because it's a lifetime commitment to treating pain in that particular individual. But unfortunately, sometimes that does occur. Next slide. One thing that was previously used frequently and is less so now, there is a surgical approach to fixing the scapula. It's a big deal of surgery. It's a highly invasive procedure. And there are a minority of patients that do benefit from that procedure. If you manually fixate the scapula you can achieve increased range of motion. Those are the people that can help -- that would benefit from that particular surgery. But like I said, it's not very frequent that occurs nor is -- nor are there many centers around the country that perform that procedure. But beyond that surgical fixation, there's really nothing else that can help with shoulder or arm function. We've tried tape and other type of mobility devices, and it's very difficult to achieve increased mobility of the shoulders. Just because of the mobility issues that occur with any type of stabilization. Next slide. For the legs, this is again a survey taken from that same national registry of myotonic dystrophy and FSHD patients and family members. And you can see the frequency by which individuals with FSHD use a leg brace, which is pretty common, cane or wheelchair more common than both myotonic dystrophy type 1 and type 2 in that particular registry. So commonly, at some point during the disease course, people will require some sort of assistive device. Next slide. And then interestingly enough, actually, this is a study here that shows that aerobic exercise has been shown to improve endurance and reduce fatigue. It doesn't change the overall course of the disease, and that benefit does diminish as disease progresses and function declines. But it does provide at least some improved quality of life. We do caution patients to avoid weight-bearing exercises. Again, because if you think about your scapula and the muscles within the scapula is being wasted, in FSHD, you're now really relying a lot on that joint ligament to provide the torque capability. And so you're putting an extra load on something that's already weak. And so people have been injured in the past with weight bearing exercises. But aerobic activity is helpful. Next slide. And that functional decline overall, everything I just said, really does require an annual monitoring at a minimum. The patients come to clinic at least once a year, if not more frequently. So we do measure pulmonary function at baseline and with symptoms, retina monitoring in appropriate patients. We always screen for patient -- for pain, as I mentioned earlier, and then same thing for hearing screening at least on an annual basis. So it's not surprising that in a chronic progressive condition that where people progressively lose independence that people are pretty excited about the idea of a disease-modifying therapy. So this voice of the patient report underscores the need for a therapy to slow or stop disease progression. Over 62% would take a therapy even if it could just slow the disease progression a bit or stop the loss of muscle function. Obviously, the 32% would want a therapy if it could help them regain strength and or muscle function. But you can see from the quotes and this is consistent with my clinical experience as well. because it's a slowly progressive condition. If you're exploring the disease progression by even 10%, that's another 5 to 10 years of somebody being able to walk over a lifetime. So it is actually a big deal to achieve a disease-modifying therapy. Next slide. And what would that therapy look like? So it could be ideally be oral, safe and well tolerated and then disease modifying. So either just slow or stop disease progression. And the therapy with this profile could be used immediately after diagnosis. So it is unclear to the extent to which muscle recovery with long-staying damage would occur. So early treatment is probably essential. Next slide. So in summary, this is a progressive and debilitating disease. There's no approved therapy. It's really diagnosable and current management is limited to symptomatic treatments, assisted devices, exercise and surgery. But that is safe, well tolerated and disease-modifying therapy would be life-changing for therapy. So I'm very excited to see this program continue to move forward. And thank you for your time today.

Thank you, Dr. Johnson. Over the next few minutes, I'm going to share information about losmapimod, a small molecule that we are developing as an oral therapy for FSHD. I'll briefly touch on the mechanism of action and remind you of the existing clinical data that we have, demonstrating losmapimod's effect in slowing disease progression. Importantly, what I'll do is put together these data and outline how they have informed the design of REACH, a registration trial of losmapimod for the treatment of FSHD. Dr. Johnson noted that the cause of FSHD is the aberrant expression of DUX4. Let me take a moment to explain that a little further. DUX4 is a homeobox gene that is required during embryogenesis. But when it's aberrantly expressed in skeletal muscle, it triggers an immune cascade and this leads to muscle cell death and replacement by fat. Our proprietary discovery engine FulcrumSeek discovered that if we inhibit p38 MAP kinase, we also inhibit DUX4 expression. Losmapimod is a p38a/b selective MAP kinase inhibitor. And we and other independent labs have shown that losmapimod at clinically relevant concentrations in preclinical in vivo and in vitro assays decreases DUX4 expression. Importantly, DUX4 is already supported by a database of exposure in over 3,600 people, and we have exposed over 100 people for more than 2 years to losmapimod, really well characterizing the safety and tolerability. So let's move to the next slide. I'd like to remind you about the ReDUX4 trial. We ran this trial a few years ago, and we brought forward the data from that trial last year. Now when we ran DUX4, we had 2 goals in mind. One was to better understand clinical research methodology to teach us how to best study FSHD. How long would trials need to be? What instruments are the most sensitive to detecting change? But also, of course, we wanted to look at the efficacy of losmapimod in slowing disease progression in FSHD. What we found was the following. Losmapimod helped patients to maintain function as measured by the reachable workspace, and you'll hear more about that later on from Dr. Jay Han. Losmapimod also maintained vessel health by slowing the infiltration of fat into muscle. Patients importantly recognize this benefit as measured by a quality-of-life scale, the patient global impression of change. And of course, we've looked at safety and tolerability and found that the safety and tolerability profile that was generated in FSHD patients was similar to that in the existing database. All of this was achieved with only 80 patients in a 48-week study. So when we move on to the next slide. What I'm outlining here is what did we learn in ReDUX4 that we are applying to the REACH study? And later, I'll walk through each of these important outcome measures. First and foremost, a question across the industry and clinical trial methodology was how long do we need to study patients to be able to demonstrate disease progression. And what we found out from ReDUX4 is that 48 weeks is a sufficient time period to be able to see disease progression over a number of different outcomes. So REACH will be a 48-week trial. When regulators look to approve medications, what's really important to patients and what's really important to regulators and payers is can patients maintain function and how do they feel while taking the medication. We utilize reachable workspace as a measure of function, and we show that, in fact, function is maintained in people receiving losmapimod and function declined in a 48-week period in patients who were receiving placebo. Reachable workspace will be our primary endpoint. I'll review reachable workspace in a moment, but after my brief talk, Dr. Jay Han will outline in detail the utility of reachable workspace and its development. As I mentioned a few minutes ago, muscle fat infiltration is [ home more ] pathology for this disorder. What we found in the ReDUX4 trial was that losmapimod stopped muscle fat infiltration in patients receiving it. However, patients who received placebo during that 48-week trial did continue to accumulate fat in muscle. We will be including muscle fat infiltration as a secondary endpoint in the program. And finally, I will outline data from ReDUX4 showing that patients recognize the benefit of receiving losmapimod. And that same scale, the PGIC will be included in the REACH trial, as well an additional scale of activities of daily living, the neural claw. And these will be secondary endpoints in the REACH program. Let's go on to the next slide, and I'll begin to just briefly review some of the data that we generated in ReDUX4 and how it's being utilized in the REACH trial. So first, let's talk about muscle fat infiltration. What you see on the left-hand side of the graph is muscle fat accumulation as measured by MRI in patients who entered the trial with muscle fat of between of 10% and 50%. So these patients were focused for us because they represented the group of patients that we thought would be most likely to show disease progression in 48 weeks. And in fact, that was the case. You can see on the left-hand side, the gray bar indicates that people receiving placebo over 48 weeks continue to accumulate that into muscle. The orange bar shows that losmapimod slowed or even stopped that infiltration upside. Now if we move over to the right-hand side, this graph is interesting because what you're shown here is the effect of losmapimod in patients who entered the trial with normal appearing muscles. So the muscles that we looked at here are between 0% and 10% muscle fat infiltration. We learned 2 important things: one, in 48 weeks, even normally appearing muscles continue to have fat infiltration and losmapimod stops this infiltration. We'll go to the next slide, and I'll introduce the concept of reachable workspace. When Dr. Johnson outlined what was most important to patients, you saw that over 95% of patients report that upper extremity function is incredibly impactful on their day-to-day living, function and the maintenance of independence. Now if you see the avatars here on the left-hand side. The scale itself reachable workspace is fairly intuitive. These avatars show patients reaching their arm of above their head. If you cannot reach your arm up above your head into what is marked as quadrant 3. Think about the ability you have to pull your own hair or wash your hair and what that means in terms of your independence. If you can't reach quadrants 2 or 4 you're probably unable to unbutton and button your shirt. You can't get dressed in the morning before you get undressed and you require help for that. And when you think about quadrant 5 reaching behind, think about your wallet in your back pocket or your cell phone. What we learned about reachable workspace as a functional outcome is, one, it's intuitive. A patient sits in front of a video camera and reaches their arm into all of these different quadrants. The surface area that patients are able to access is captured by video. So it's not qualitative. It's extremely quantitative, reliable and reproducible. The question that we asked in the ReDUX4 trial was in 48 weeks, will reachable workspace be able to demonstrate a loss of the area that patients can access and will losmapimod slow or stop that. And the answer to both of those questions was yes. You can see here on the graph on the right, the vertical line represents baseline. So when you look at black dots, you can see that in both arms, the nondominant arm and the dominant arm, patients lost the ability to access surface area. Well, not only did losmapimod patients retain that ability, but actually, in some cases, actually gained the ability to reach the surface area. The next slide shows a graph of this exact same data that's a little bit easier to understand. Here, you can see each arm, the dominant arm and the nondominant arm. And this graph shows you the annualized rate of change over the course of the 48-week study. Notice that in both arms, patients receiving placebo had 4% to 10% change in the amount of relative service area they can access. The orange bars clearly show that losmapimod patients retain their ability to reach these surface areas and also, in some cases, improve it. This is important for us because as we met with regulators, they were convinced of the fact that reachable workspace is a functional endpoint because these activities of daily living require the utility of upper extremities. Now the next slide shows how these 2 data sets go together. What is the relationship between the infiltration of fat into muscle and reachable workspace? Now on the Y-axis, you have scores on reachable surface area, relative surface area. You can see that as that decreases, so does the muscle fat is -- the muscle fat infiltration increases. So the more muscle fat infiltration that patients experience, the less well they were able to perform on reachable workspace, which means that they could reach less relative surface area and came 1 step closer to becoming dependent. The final data point from ReDUX4 that I'd like to describe to you is shown on the next slide. And this is -- the question is, did patients recognize the benefit of losmapimod. This was performed with this very simple but sensitive scale called the Patient Global Impression of Change. It's 7 points and a 1 or a low score means patients are improving and a high score means that they're getting worse. Look at the graph on the left-hand side, you can see that many more patients reported feeling improvement while receiving losmapimod. Now keep in mind, the goal of this therapy is not to improve function but it is to maintain the functions that patients already have. You can see on the right-hand side, approximately 20% more patients represented getting worse when they're receiving placebo over 48 weeks, no patient who receive losmapimod in the 48-week study reported getting much worse. This next graph brings together reachable workspace and looks at its relationship to how people felt. On the Y axis, you can see that there's a percent change from baseline and the relative surface area that patients can access and on the X axis is the patient global impression of change. Now remember that a small number means that patients are doing well. Look at the very left-hand side of this graph, patients who reported being very much improved, also saw improvements in RSA. On the other side of this graph, patients who reported getting much worse also decreased in our score reachable workspace, which means that they were able to access much less relative surface area. So let's go to the next slide. I've already shown you that losmapimod has slowed or even stopped the infiltration of fat into muscle. This has resulted in a slowing of functional disease progression as measured by reachable workspace and that patients recognize that benefit. This is all on the backdrop of a well-characterized safety and tolerability profile. The majority of adverse events in the REACH trial were mild to moderate, no patients left the trial for adverse event. And the adverse events that were experienced did resolve with continued treatment. It's interesting to note that we currently have an open-label extension study associated with ReDUX4 and we have 99% continued participation in that trial at the 96-week mark, which really speaks to the tolerability of the drug because patients continue to be widely take it. I believe the next slide is my last -- one of my last slides. And this has really put together the story that we generated in ReDUX4, the important data set and how we will apply this data to the REACH trial for registration for the treatment of FSHD. In designing the REACH trial, we continue to speak with patients, with regulators, with key opinion leaders and with payers to ensure that we could conduct a trial that was recognized as valuable to a variety of stakeholders that will be involved in FSHD. The REACH trial will be 48 weeks in duration. There will be only 2 arms placebo or losmapimod, 15 mg twice a day. This is exactly the same as in the ReDUX4 trial. We will have approximately 230 subjects enrolled. Patients who have a diagnosis of FSHD1 will be able to participate as well patients who have a diagnosis of FSHD2, the age criteria between 18 and 65 years old. The primary efficacy endpoint for the REACH trial will be reachable workspace, a quantitative measure of function. The inclusion exclusion criteria for REACH will be almost identical to the ReDUX4 trial. However, there will be a slight modification. We will enrich the population on reachable workspace, to ensure we get those patients in who are most likely to demonstrate disease progression. The secondary endpoints in the REACH trial will be muscle fat infiltration. The Neuro-QoL, which I've already mentioned, this is a qualitative measure of upper extremity function. The patient global impression of change and, of course, continue to look at safety and tolerability. As we prepare for the commercialization of losmapimod, we'll also be probing on health care utilization by the use of several questionnaires. So I believe that the next slide summarizes what I've told you today. Losmapimod targets the root cause biology of FSHD by decreasing DUX4 expression. We know that losmapimod has already demonstrated efficacy across a number of important outcomes: function, disease pathology, benefit to patients, and safety. All of this data as well as interaction with a number of stakeholders was taken into consideration as we design the REACH trial. REACH has been optimized to show benefit on these same measures, muscle health, function and patient reported outcome. We intend for REACH to serve as the basis for approval of losmapimod for the treatment of FSHD. With this, I'll end my comments and thank you for your interest in the program. We're incredibly excited to bring losmapimod forward to patients in need and look forward to starting the trial in the second quarter. And with that, I'll turn the talk over to Dr. Jay Han, who will give you more in-depth information on reachable workspace. Jay?

Thank you. I'm happy to discuss today with you about reachable workspace, a sensor-based and innovative quantitative outcome measure for upper extremity. I'll be sharing the experience of developing RWS as well as some data that would be relevant for FSHD and for the planned clinical trial. Next slide, please. This is my disclosure. Next slide. So advances in neuromuscular research are driving the need for sensitive and quantitative clinical endpoints. This is exciting time for neuromuscular disorders. After many years of studying the mechanism of disease and elucidating the pathophysiology, a viable target has been identified for drug trials. There are some exciting clinical studies coming online, utilizing small and large molecules, drug candidates, gene and cell therapies, assisted devices and robotics. However, what this all has highlighted is a need for effective endpoint. How do we know what therapies actually work and are effective. The endpoints will identify the -- improve the monitoring of the disease and severity of the progression as well as inform us about the characterization of the natural history. Next slide, please. So even though the cutting-edge therapies are being developed as we speak, and the tools and outcome measures that will evaluate these cutting-edge drugs are lagging. As you can see here in the picture, there are a variety of outcome measures. You can see the stopwatch, the tape measure. Goniometer that measures the angles of the elbow and the shoulder, strain gauge that measure the strength. And then also, you can time how quickly a patient moves a small peg from one place on a table into a put -- placing it into a hole, how fast that patient can stack cans. So these are very elementary and basic outcome measures that are available in the landscape of outcome tools for neuromuscular disorders. So about 15 years ago, our team actually utilized this as a motivation to come up with a connotative sensor-based and leveraging the technology that were being developed. Next slide, please. So what do we measure then? Then we can look to the various neuromuscular disorders and FSHD as many speakers previously have mentioned facioscapulohumeral muscular dystrophy as the name implies, affects the shoulder muscles and limb-girdle muscles greatly. It affects the pelvic and the hip girdle muscles, too, and also the hand muscles but to a lesser extent and much later in the course of the disease. So we wanted to look at the -- how the upper extremity functions and reachability and reachable workspace became a target. Next slide, please. So this slide shows the general idea behind the reachable workspace, a patient would be moving their arms in space, different quadrants. And we would be utilizing a motion sensor to detect the trajectories of the arm as well as the X, Y, Z coordinates of those movements. So a sensor would provide those data point, a cloud data point for movement and trajectories. Here, we've actually tested many different devices and sensors, but we've settled on Microsoft Kinect. Many of you are aware and know Microsoft Kinect sensor. But the X, Y, Z coordinates and the data that we gain would inform the algorithm and the software behind the sensor to reconstruct a person's individual reachable workspace. So you can see down in the bottom right corner, the reachable workspace which essentially is kind of a shell of a hemisphere. If you had a full range of motion in your shoulder and strength that you could reach into different quadrants and it will be spherical in essence. You can put an origin at the shoulder and divide the reachable workspace into quadrants, as people have talked about. And also from the side, you can see the posterior lateral lower quadrant, which is important for reaching back into back pocket, but also self-care and your toilet work and self hygiene. So these quadrants can be very quantitative and also objectively measured. The actual unit for reachable workspace is called RSA, relative surface area, which is the surface area of the eggshell of your hemispherical reachable workspace, normalized by each person's arm length. Next slide, please. So reachable workspace is quantitative, noninvasive, intuitive with that simple patient interface. As you can see on the left panel, the picture, that's the mobile cart system that we have. It's very simple in its component. It has a large TV, has a computer and Microsoft Kinect sensor. That's all it takes. And the patient can either be in a wheelchair or sit down in front of it and follow the protocol of moving the arms and the reachable workspace would be generated. Person on the right, the picture on the right shows the wall-mounted system with the patient and power wheelchair undergoing the reachable workspace protocol. So to reiterate, it's simple, the low cost, low maintenance, it's quick. It takes about 1 minute to evaluate each arm. And there's no wires, there's nothing that patients have to wear. There's no sensors that they are being attached at the body. So it's unobtrusive and relatively low burden for patients. And when I explained the reachable workspace, the concept and what we're attempting to do with patients, it's quite intuitive for patients to say that, oh, I see, this is my reachability. This picture shows how far I can reach into different quadrants and I can actually make the connection that reachable workspace would be related to my activities of daily living. Next slide, please. Here, I will go through a series of data in developing the reachable workspace. From the beginning, some 15 years ago, when our team embarked on this development of reachable workspace. We wanted to be very methodical and systematic in testing our new system, testing its reliability, testing its validity, sensitivity and also clinical meaningfulness. So in the beginning, in the very first stages, we wanted to check the Kinect's ability to capture reachable workspace against a very sensitive full-scale motion capture system. And as you can see on the upper panel A, head-to-head, the full-scale motion capture versus the Kinect reachable workspace, the amount of reachability a patient undergoes is very comparable. Next, we wanted to test and retest reliability that's how reliable and how reproducible is the data from one time point to the next time point. So the bottom panel A shows that one time point versus another time point, and it actually is very reliable. And we tested this in multiple different neuromuscular conditions, different patient groups and the reliability has shown to be robust. In FSHD population, in particular, the correlation factor is 0.95. So extremely high reliability. Next slide, please. So in this slide, let's focus on the bottom, the -- highlighted by blue, this is a radar plot showing the reachable workspace of FSHD -- group of FSHD patients. The -- you're looking at the frontal projection. So the quadrants are represented 1, 2, 3, 4, upper lateral, lower lateral, upper medial and lower medial. And what you can see there in the dotted line, black outline is a reachability or reachable workspace of a healthy normal individual. And you can see how that almost gets out to the full circle into a different quadrant. FSHD patients are represented by the black outline, and you can readily see that the reachability into the upper quadrant is significantly impacted with the relative preservation of the lower quadrants. But the amount of reachability into the upper quadrant is significantly reduced compared to other neuromuscular disorders at Duchenne muscular dystrophy, the Becker muscular dystrophy or even motor neuron disease such as ALS that we can see those -- what those reachability and reachable workspace looks like for those populations up above. Next slide, please. So we've tested the reliability of the -- and the test retest reproducibility of the reachable workspace system. Then we wanted to see if the reachable workspace also correlates with the current clinical measures, how we determine how severe FSHD patient is clinically whether they're mildly affected, severely affected. So head-to-head against those clinical outcome measures, the reachable workspace was also highly correlated. Look at the picture on the A, that's again a radar plot of the reachability into 4 quadrants. The black dotted outline is the healthy individual, what a reachable workspace would look like. And as the disease progresses and gets worse, from blue to red to the green to the purple and yellow, you can see how the reachable workspace contracts as the patient's disease worsens over time. So this is a very nice way to illustrate and show the -- how the reachability changes over time for FSHD population. And the B is a graph against reachable workspace against the FSHD scale in a graph form. And again, you can see that as the disease worsens, moving from left to right, the RSA decreases, the total reachable workspace decreases. But importantly, you can see -- you can appreciate readily how the blue and the red, these are the upper quadrants, reduce -- are reduced significantly. Next is -- next slide, please. So then next is we wanted to measure whether reachable workspace also correlated well with strike measures, the raw strength of the upper arm and the shoulder. All these data that I've shared with you so far have been already peer-reviewed and published, and this one is published in a journal where the reachable workspace correlates well with strength measures. Next slide, please. So reliability and validity, now we wanted to move and test the sensitivity of the reachable workspace. Does reachable workspace is able to detect small changes that are happening in patients and how do we improve that sensitivity? This graph shows that applying a small weight, wrist weight, such as 500 grams in the wrist can really bring about the subtle differences in reachable workspace in patients. This data from actually Duchenne data, but a similar data can be seen in FSHD. So let's focus on the left dots, the green, the red and the blue. You see how they're all bunched up together. So this would be a healthy individual, the green, how their reachability is shown on the RSA graph there and very mildly affected muscular dystrophy patients, so Duchenne and Becker both, group of them. Essentially, you cannot tell them apart. The reachability, reachable workspace is the same. However, in a no-loading condition -- however, when you apply 500 grams of wrist weight, the patients that are healthy or the healthy individual will be able to maintain the reachability, whether it's 500 grams or 1,000 grams, as you can see, the line is horizontal green line. But the subtle weaknesses will be brought on by applying the wrist weight because of the leverage that with even a small amount of weight at the wrist, puts tremendous amount of torque or increased the amount of torque and force pressure on the shoulder girdle. So if you have weakness in the shoulder area, then you will start to lose reachable workspace and reachability. So that's actually nicely shown as the blue line. Initially, it looked like they had a very good reachable workspace, however, with applying the weight that it begins to separate from the healthy individuals' reachable workspace. So next slide, please. We then wanted to look at the sensitivity of the reachable workspace over time and can it follow a patient through the years. As we know, FSHD is a variably progressive disease. And it may take years or decades for them to be impacted functionally. But here, we just published data in the Journal of 18 subjects with FSHD in a 5-year study where we followed several of them for a long period of time. As you can see on the top row of one particular patient examined that 2012 all the way through 2016, you can see the reachable workspace changing and declining with no weight. The same patient with the wrist weight, you can see how the reachability and reachable workspace declines over the years, you can see in the bottom row. Next slide, please. The same data, if we take a deeper dive into this longitudinal natural history study of the patients. And just looking at the upper climate, the quadrant 1 and quadrant 3 and separating it off between dominant and nondominant, you can see that there is a significant -- statistically significant and clinically significant change in their reachability, especially in the upper quadrant. And quadrant 3, so that would be the upper lateral quadrant and the dominant side is more affected to the tune of approximately 9% per year. So your upper quadrant, you're losing almost 10% a year of your reachability into upper quadrant. If you look at subgroup of patients that have the reachability of 0.2 to 0.7. Roughly, that would be about 20% of your total reachability or 70% of what you can do compared to a healthy individual. So if you have -- if you're in that group, we believe -- we think that, that's a group that's likely to decline more rapidly. Mildly affected, very mild FSHD patients would maintain their reachability for many years, and they wouldn't change. And a very severely affected individual below the 0.2 level, they already lost a tremendous amount of reachability, and it would still be very flat and stable. But we believe that this group of patients in this 0.2 to 0.7 range, they would be changing rapidly. And as you can see, the quadrant 3, the dominant and nondominant side can change over a year approximately 8% to 14%, nearly 15% per year. So these patients may likely be the candidates for drug trials. Next slide, please. So what I've shown you through all the data so far is the reliability, validity, sensitivity. Now we wanted to look at the clinical meaningfulness. What does reachable workspace actually means? Does it have impact? Does it have any correlation to what a patient can and cannot do. So we wanted to correlate it to a patient-reported outcome measure called Neuro-QoL, Upper Extremity Module. This is composed of 20 questions asking patients whether they are able to do or what kind of help do they need for brushing their teeth or washing their hair, combing their hair, buttoning their shirt, taking -- putting on and putting off shirt -- taking off shirt, pulling up their pants and so forth. So when you correlate reachable workspace with the Neuro-QoL, you have a very good correlation. So you see the Neuro-QoL score on the right, on the graph, the axis, Y axis versus the total reachable workspace, there will be RSA and the X axis. So let's focus on the top dots and the line, that's the blue. So if you look at all the questionnaires from Neuro-QoL of the activities of daily living with the reachable workspace, it correlates highly to the tune of 0.76. That's pretty high. And if you look at the orange dots and the graph on the bottom, that would be looking at the subgroup of questions that are particularly important for proximal upper extremity function. The correlation is even higher at 0.839. Speaking with experts and who developed the Neuro-QoL questionnaire and also the experts who are -- have been dealing with PROs, patient-reported outcome measures, this degree of correlation of reported function with an outcome measure such as RSA, is thought to be extremely high. So now the reachable workspace appears to have a very high correlation with actual patients' activity just daily living. Next slide, please. Looking further into the different questionnaires, the questions with the activities and mapping it to the reachable workspace quadrants, we can actually appreciate that reachable workspace and different quadrant have a high correlation with the hygiene activities, dressing activities and feeding activities. And in general, the hygiene activities are important -- correlated to the upper quadrant, and the dressing, the lateral quadrants and then feeding the lower lateral quadrant. You can imagine, we don't raise up our arm above the shoulder level to feed ourselves. Our arm essentially stays lower down. And then we use our spoon or fork to pick up food and bring it to mouth, but a lot of it is actually done with the elbow and the wrist range of motion. But the shoulder, the proximal range of motion remains in the fourth quadrant. Next slide, please. And we wanted to see if reachable workspace and RSA, can it inform us about independence and dependence, how much work or how much of the mutual workspaces need to be there for you to be independent. So we have a threshold or cut off for a reachable workspace to determine whether a patient needs help or they can actually do a lot of activities of daily living independently. So this is a little bit of a complicated graph there, but I'll take you through. Let's look at the graph on the A panel on the left and has the colored bars there, and those represent the activities such as using spoon to feed yourself, pick up clothes, pull up pants or to put on shirt and take off shirt, so forth in these different colors. The left side panel would be the patients who reported having significant difficulty with these activities and either they couldn't do this or they need a significant help. On the right hand side of the graph A is patients who reported being independent with all of these activities that they are capable of doing them day to day. And on the y-axis, you see that there's a threshold, a cutoff of 0.7, that if you are able to maintain your reachable workspace, about 70% of your total reachable workspace, then you are essentially going to be independent with carrying out with these activities, whereas if you're below that, then you will need a significant help or are unable to do that. The B panel is similarly organized, but it's really just focusing on the upper quadrants that if you're just looking at the upper quadrant, if you are able to maintain at least a 40% of your upper regional reachability quadrants, then you're going to be independent with these activities. And if you're below that, then you will be needing a lot of help or unable to do that. Next slide, please. So I hope that there's -- I've shown you some data showing good reliability, test retest reliability as well as the validity of the reachable workspace that it correlates well with the currently used clinical measures as well as sensitivity that it is capable of protecting small changes in reachability over time and the clinical meaningfulness that reach of our workspace has a clinical meaning for activities of daily living. It's CE Mark and has FDA Class I. It's ready for clinical use in the clinical settings as well as in clinical trials. It's well-characterized now in multiple studies and published data in engineering literature as well as in medical literature and outside investigators have been able to reproduce our data also. It's been used not only in neuromuscular conditions and FSHD, such as Duchenne and Becker and motor neuron disease as ALS, but now the investigators around the world have been using it for stroke rehabilitation recovery and tracking for orthopedic surgery and cases and musculoskeletal injuries that relate to shoulder, breast cancer rehabilitation after patients have received radiation to the shoulder or the torso and their limited range of motion. And also the nerves that control the shoulder, those cases all have been showing -- the reachable workspace has shown utility in those case studies also. So it's highly correlated with the ability to perform activities in living and maintain independence. And it has been used in the clinical studies that you've heard before with Fulcrum's Phase II study, an open-label study. We're excited to participate in this study and help patients gain function. Thank you very much. This ends my presentation, and I'll be available for a question-and-answer session.

Thank you, Dr. Han. Dr. Han, Dr. Dunn and Dr. Johnson has stated FSHD is a debilitating, relentless and progressive disease and someone even say insidious disease. And we're just proud at Fulcrum to have an opportunity to bring to market the first therapy for FSHD. What makes it so exciting to us is that not only will it be the first product to be launched in this area, but potentially also a disease-modifying therapy. That in of itself is transformative for patients within a desperate need of a therapy, that's just the beginning. And also from physicians who had nothing to treat these patients since the beginning as well. Next slide. Now for Fulcrum, there are several drivers or value drivers, as we call it. Number one, a high unmet need for a disease-modifying therapy to slow the progression of the disease. Number two, a highly addressable patient population. We begin the process now of looking across the globe to map out where these patients are residing to ensure that we've taken the time to figure out where all the key centers are in the United States, but also in Europe. This is a highly addressable population where unique go-to-market models are going to be necessary with the fit-for-purpose intent. Now of course, a chance to be first-to-market is always good. But the chance to be first-to-market with a 4- to 5-year head start is even better. And what also is great about that is, is that with a drug that was losmapimod with the potential to be a first-to-market disease-modifying therapy, which is focused on functional endpoints, raises the bar substantially for the community. So anything coming behind us, will have to meet that bar. So we're really excited about that to bring up therapy potentially to a market that will help patients in a very discernible way. And of course, fast track status never hurts, having the regulators work with us closely and to align our reachable workspace as a very important attribute for patients to be measured is critically important to us, but also very excited for the community. And of course, a committed and engaged community. Since our founding in 2016, FSHD has been our DNA. We partnered with this community in a very deliberate way over the years, and we'll continue to. This community means a lot to us. We've had a chance to interact with them in multiple different forms, and we'll continue to do so going forward. This is a highly intelligent, passionate, engaged community that we feel a responsibility to ensure we do whatever we can to bring losmapimod to market. And of course, last but not least, 3600 patients, not been in multiple disease areas, rare, ultra-rare diseases, specialty, very rarely have I had 3,600 patients exposed to a product before you even launch a product. Later, they included a pivotal trial. So we're excited about the REACH program and the value it's going to bring to patients and also caregivers as well as ACPs as well. So we're really excited about the potential of losmapimod. Next slide. Now one of the key endeavors that we wanted to undertake was to really understand the epi. And most of you have probably seen 4.97 per 100,000 or maybe 1 in 8,000 or 1 in 20,000 that comes out to about 16,000 to 38,000 patients in the U.S. We've done the work using the recently minted ICD-10 code. We've done some claim analysis data as well as some efforts around cabalistic modeling and discovery, there's really between 25,000 to 34,000 patients in the U.S. We're doing the same thing right now in Europe, which we're excited about. And our intent now is a go-forward, map these patients out to respective regions of the U.S. as well as the states and then eventually get down to each zip code and align patients to respective neuromuscular centers. That will help us tremendously to insight our go-to-market model to ensure we're providing the maximum service to patients with losmapimod available to patients. What we're also excited about is the fact that where we do have this product available, we're focusing on what's really most important reachable workspace. Reachable workspace, as you will hear later on, is tangible. It's real. Patients get it, it's intuitive. And again, it's functional. We're not relying solely on a certain marker or a biomarker. We're focusing on what's really important to patients. And that means not to me as a commercial head is to really make sure that whenever we come out with patients understand it, appreciate it and is applicable at launch, which is very exciting for us as well. Next slide. Recently, we conducted some market research globally, particularly in the U.S. and Europe. And there, we ask physicians, help us understand what are your unmet needs, what are your true unmet needs in FSHD. And not surprising, the first thing that came out of their mouth was disease-modifying therapy. And that was the same for the U.S. as well as in Europe as well as Japan as well to be quite honest. Each one said disease-modifying therapy. Number two was about slowing the progression of the disease. That's clear because you've heard from Dr. Han, Dr. John, Dr. Dunn, this disease is insidious. You have patients who were born relatively normal, and they're having great life, they're playing sports, they're hiking, doing those basic things that we all take for granted. But nevertheless, if there's a family history, they know potentially within 5 to 10 years, all can change. And their entire life can be [ upcarted ] and, therefore, they have to endure disease and possibly go into either braces or possibly cane or wheelchair and not be able to do the basic things like brush your teeth or comb your hair. If you're a painter, you can't paint any more. So it affects your livelihood. There are so many things that are affected that we take for granted as healthy individuals, this patient community deals with every single day. So the chance to actually change that trajectory means a lot to us. So for a physician to say they want disease-modifying therapy and slow progression is critically important. Of course, safety is always key, as I mentioned already, 3,600 patients have experience with this product as well as our clinical trial REACH will play a long way in helping to make sure we feel very comfortable that this is effective but also a very, very safe therapy as well. Next slide. Now with patients, we took a different approach. We said, well, let's talk to patients who have no mobility issues and those who have mobility issues. And we're asking the exact same question, what are you looking for in a therapy? When it came back to us, they were talking -- really focusing on slowing disease progression. As you've heard, this is just what keeps patients up at night. This will keep parents up at night. And adults, in general, not the fact that they all know where 5 years outlying, 10 years outlying, think of possibly being in the wheelchair or some type of device is necessary. So be able to slow it down and get that time back is so critical. And for us, it's also important because we partner with the community for the years, we've heard their stories, we talked to them. We've listened to them and they've shared their insights. They actually helped us to actually design a REACH trial and taking a tangible comment and saying, let's figure out a way to ensure that the PRO that we put in a trial relates specifically to the needs of the actual patients. And that was so critical for us to go by doing that. But you can see from the patient perspective, there was really about whether there was no mobile devices needed or devices needed. For them, it was really about slowing disease progression. But then when there was 2 or 3, it was about mobility or upper body function. That was critically important to them, making sure that if you don't have any issues right now, obviously, maintain and keep that upward mobility available to you, or if you do have issues, maintain as much mobility as possible is critical. And of course, safety as well as always in the back of patient's mind. You want a safe therapy and you also talked about that as well. So we want to make sure that as we go forward with the program, we continue to focus on those real tangible things that make a difference to patients. Next slide. One of the things that we've decided to do over the years, I mentioned was to anchor down on patients and to really talk to patients about really what's driving you. And in the middle of last year, 2020 actually, during the pandemic. The PFDD meeting was held, which gave patients an opportunity to really get in front of FDA and discuss how this disease truly manifested itself. It was powerful, it was emotional, but just as important, it was meaningful, and it gave patients the chance to push back what is [indiscernible] being slowly progressing. And again, that's the serious part is that if you think about it, you're a normal for the first decade of your life and you're enjoying life and all of a sudden, you see something happens to your body. You start to feel weaker. You have a hard time brushing your teeth, combing your hair, do those basic things that Dr. Han alluded to, that's not fully progressed. That's actually even scarier. It's almost like you see a train coming out to you, and not sure if the train is 5 years away or 10 years away. What you know is it's coming and you have no way to stop it. But they were able to talk to the FDA in very, very clear terms by how this disease is affecting them and impacting them. And that was a very powerful way. So I think put on the radar screen, exactly why this disease needs a therapy option to treat it. Well, going beyond that meeting, we sat down with a few advisers and we say, listen, that was a great meeting, but tell us your story, let's figure out where we put this in writing. So some of our advisers sat down and wrote out a white paper. And I do implore you if you have an opportunity, read this. It's powerful, it's clear and script goes beyond surveys. It truly gives you a glimpse into the patient's mindset of how this disease affects them on a daily basis. It's really important. If you get a chance to read it, I would definitely implore you to do so because it really does qualify and quantify the burden these patients are going through a day-to-day basis. And the hope of a disease-modifying therapy that focuses on a functional benefit like RWS and illustrating that impact is critical for them and goes well beyond any other biomarker that can be used to assess because this really gives them a sense of -- this is how it's going to impact my child as well as myself going forward. We're also, of course, partnering with our -- with a community around PROs. We're doing work with them throughout HUR in both the U.S. and the U.K., very, very, very important things for us to continue to do and to make sure that the patients' voice is a part of our clinical trial. As I mentioned, the REACH trial wasn't just done in isolation within the Fulcrum confines, it was actually incited very deliberately from patients. So the PROs that are in there, changed from patient generation conversations and really wanted to make sure we have that incorporated into our plans. Another way we incorporate patients' feedback into our strategy and our programming is through co-creation. The co-creation have been that we do at Fulcrum, which we feel is very, very critical. Co-creation allows us to fundamentally sail with patients and not at the tail end, but really focus on patients at the sort of at the outset and walk with them throughout the journey of, hey, here we are. Here's a program we're thinking about pushing forward. But I really want to get your thoughts and your feelings about, does this makes sense? Does it resonate? And that allowed us to go all the way through to the final product to ensure that we're speaking specifically to patients in a very clear and accurate manner. So we're really excited about this as we go forward with our effort around disease, education and all the other things we're doing, Congress is going forward and just intact with the community. This is a great way to think to make sure that we are really speaking specifically to the patients' needs, desires and wants as well. Next slide. The next slide, I have a series of quotes. And I really want to take a second to read these quotes. Just kind of look at them on the screen. And I want you to read them. Because the reason why -- I want to reason because they really do signify how these patients are truly feeling, what's going through their mind. What type of emotions are they experiencing along the way. And I think it's critical for you to kind of see that and hear that. So I'll take a second and let you read this quote, and I'll come back with new comments. Okay. Just to underscore as to relevancy of the reachable workspace endpoint. It is meaningful, it relates directly to what patients contend with and manage each day just to function in life. It is specific and is targeted to real life function. This is sort of a crystallization of why RWS is more important because it's real. And I've been in multiple disease areas where we use biomarkers that patients, physicians, payers, everyone was trying to figure out what's going to be the total outcome as all saying, is it going to translate to actual benefit? What they're telling you upfront, this is what this is all about. Next quote. This quote is probably because it speaks to the progressive loss of function a patient loses a year at the year, as Dr. Han mentioned, up to 9% or 10% progressive loss, that's aggressive. That's relentless. And that's something that's very scary for a lot of patients. It's scary because you know -- as I mentioned earlier, you know something is coming down the pipe and you had really no idea how to stop it. Now you can just hope and pray that it will slow down. You will have an advanced best coast, which is super fast or a slow coast which is very, very methodical yet pragmatically horrible for the patient and the patient's family. This disease is relentless. It is progressive, and I might say again, it's insidious in so many different ways. Last quote. Take a second to read this. This quote is all about loss. Patients want to regain that lost time. They want to be able to do simple things like cook, feed themselves, hold an iPad, hang a picture, pick up a child. And you think about how basic that is, to pick up your child. If you're a mother, you have a child, you're 25, 26 years of age, you'll be young southern daughter and came to pick them up. That is really just is a horrible way to be -- to exist. And we could slow that down in any way or fashion Dr. Johnson alluded to earlier, if you can catch a patient at diagnosis, get them oral therapy and maintain some function from that patient's life, that in of itself is a tremendous benefit. And they do it safely because obviously very important. So we at Fulcrum, we're just really excited. We're honored. The community has embraced us. We'll continue to work on the community in a very deliberate way. And we think this opportunity to bring an oral small molecule to market with disease-modifying characteristics is a tremendous way to elevate the expectations of people living with FSHD. With that, I go to the next slide, which is the Q&A. I will welcome back the panel of speakers, and open it up for questions.

Thank you, Mel, and thank you, everyone, for a very informative presentation and a special thank you to our guests, Dr. Han and Dr. Johnson, for educating our listeners on FSHD and the real urgency to find a treatment for this patient population. [Operator Instructions] And without further ado, let's jump in with the first question for Dr. Johnson. Dr. Johnson, can you talk a little bit about the trajectory for FSHD? Is the decline in reachable workspace typically linear? Or does it come in fits and starts? And there's a second part to the question.

Okay. So I'll answer the first part first, which is that the FSHD does experience periods of more rapid progression as it relates to DUX4 expression, which is part of what was captured in the study design of Fulcrum's Phase II clinical trial. And that, unfortunately, as the progression continues, it tends to pick up speed. Part of what Dr. Han was showing in terms of the rate of progression captures that the progression becomes faster, especially as the disease extends in duration.

And the second question, I'll ask you and then maybe Judy can jump in as well. Do you think that 48 weeks is long enough to show disease modification in a disease like FSHD?

Certainly, over a 48-week period of time, people with FSHD experience progression. When you see them in clinic, they have progression, and that's been captured as well in natural history studies. It is a slowly progressive condition. And so you need, obviously, the sign of this study captures the number of patients that you'd need to see the change between the 2 groups in this trial, but yes.

That's great. Judy, I don't know if you want to add anything to that?

Sure. I can add my own perspective based on the data that we've generated. And I think that probably the most informative data set that we have is that muscle fat infiltration in muscles that appeared normal at baseline. So in a number of the muscles that we look at, it was 0% to 10% muscle fat and in 48 weeks, those patients did progress to show muscle fat infiltration whereas losmapimod patients did not. So I, in particular, like that piece of data because it does show us that even if your muscles are normally appearing within 48 weeks, there's a significant amount of fat infiltration. That's measurable, and we can quantitate it. And most importantly, we can show the effective drug on that.

And this next question is for Dr. Han. Can you discuss what a clinically meaningful change in RWS is? And has that been adjudicated by the FDA?

Yes. That question is still being worked on. That's a very challenging question, and we need a lot of natural history data, prospective data. So that's what the field is working on. And there is an ongoing effort globally to follow patients prospectively and map out the natural history and reachable workspace is being collected, among other outcome measures. So we will have a better idea. But right now, with the current -- the data and what we know that reachable workspace correlates with function. And we know about the threshold of what reachable workspace needs to be to separate independent patients from patients who require a lot of help. But in terms of the delta, the amount of what percentage of reachable workspace RSA correlates to loss of what degree of function, that is a very detailed and sort of fine granular information that we do not have yet. We hope to gain that information through, hopefully, this study, the planned studies as well as the natural history study that's ongoing. That's been a priority for the field and the researchers in FSHD for a long time.

Okay. This next question, I will ask Judy to answer. Can you elaborate on the RWS enrichment? What will be predictive of disease progression with the caveat of a small end, what RWS data do you get if you apply the same enrichment criteria to ReDUX4?

Sure. Thank you for the question. Jay, I'll start and then perhaps ask you to comment as well. So in terms of the enrichment strategy, what we want to do to be able to do 2 things, run a trial that shows efficacy as outlined by the functional outcome reachable workspace. We do that in 2 ways: one is showing the separation of the trick between drug and placebo; and we can control that by decreasing the standard deviation in the population. So remember, this is already a fairly heterogeneous population. And our goal in terms of looking at that disease progression is to homogenize that in a way that those 2 things. One balance is the fact that we want to look at a broad group of people for whom the drug is appropriate, we believe the drug will be appropriate for everyone but control the trial by including those people most likely to progress. So when we talk about enrichment, it's very simple. What we do is we limit sort of the 2 ends, the 2 ends of the reachable workspace scale. So you have a very high score on reachable workspace of 0.7. You have a pretty high level of function. So you are less likely to show significant progression during the course of the 48-week trial. Take the other end of the scale, if you have very little function left, point 2, you are also unlikely to show further progression. So at the high end, you're unlikely to show perhaps any progression, at the low end, you're unlikely to show further progression. So what we do is we optimize the trial for those likely to show progression. In terms of how this would have impacted our ReDUX4 trial, we went back and looked at that data. And in fact, our REACH trial in these inclusion criteria were informed by ReDUX4. And we would have covered 80% of the patients in ReDUX4 with this criteria, and those were the 80% of the patients who are most likely to show disease progression.

Right. Thank you, Judy. I'll ask this of Dr. Han, how would you assess the trends on RWS demonstrated in ReDUX4 in general? And are there any physiological explanations for why above the shoulder quadrants and movements with a weight, we have shown beneficial effects.

Yes. Again, the difficult thing and challenging thing with a rare disease, relatively rare disease, FSHD is one of the most common muscular dystrophies out there. Yet if you look at the numbers, it's still qualified. So having a great data point and having lots of research data for us to make informed decision is often not there or we're still working on it. So a lot of the answers, these are great questions. And these are questions that we ask ourselves as researchers and clinicians who take care of our patients. And patients ask us, I'm not sure that I have the answer for you right now. I can guess as to why that's the case. It's -- the general idea is that the muscle is not all gone, but it's -- and it's changing slowly. And if you can do something to preserve muscle function and maintain it, then as a body and as a human being, we are adaptable. We can use competitory sort of maneuvers, we can use other mechanisms to add on to what you have. So I believe that if we have a drug or a therapeutic that's maintaining the decline of muscles that you have less infiltration of the fatty and fibrous tissue in the muscle, and then with that, the patients can actually now utilize more of their skills and other sort of neurological control or other competitory maneuver, be able to appear as so they're gaining function that I think -- that's sort of my guess as to what's happening. I don't know that you're adding muscle or you're tremendously impacting the muscle in itself at the basic level that you're improving reachability. But that's sort of how I put together. And the amount of the improvement that you see, it's -- again, it's not a lot yet you're maintaining or improving compared to a natural progression, which is relentless. So the staving off the decline and stabilizing the decline is, I think, functionally and clinically important for quality of life for patients.

And this question is again for Dr. Han and Dr. Johnson. Can you expand on the issue of pain in FSHD, what drives the prevalence? And how is it manufactured by clinical endpoints in this setting? Maybe I'll turn that over to Dr. Johnson.

Yes. I mean, I think the DUX4 expression causes muscle necrosis acutely and that probably is in some way related to the pain. To build on what Dr. Han mentioned in his last response. Beyond that, we don't actually understand what truly causes the underlying pain associated with the condition just that it's present, prominently featured. I know that many of the patient reported outcomes that are being considered for this trial would capture elements of pain associated with the disease itself.

Great. Dr. Han, this is another RWS question for you. Quadrants 1 through 4 data are very promising, but can you speak to any data on quadrant 5? And what should one expect as the natural course of the disease progresses?

Yes. So as a researcher and some of us have had experience in bench research as well as clinical translational research. I've been in research for a long time. And sometimes the good thing is we learned quite a lot about actually doing the things and there will be unexpected things that come up that open the door for new things that we didn't initially think about. And when we designed the reachable workspace, we had 4 quadrants, the frontal quadrants, but we know from how your shoulder is made and you can test it yourself. Really reaching backwards is very difficult. The way that biomechanically how your bone is put together, how your muscles are controlling your shoulder, that you cannot go beyond this way, if you're -- it's above. But however, you do -- you can reach backwards in the lower quadrant. So when we design the reachable workspace, we were cognizant of that. And so we measure the frontal 4 quadrants, but we also be sure to include the fifth [indiscernible], the lower lateral posterior quadrant. And I'm glad that we did, because thanks to Fulcrum and Fulcrum actually studies that we now know the importance of the fifth quadrant that it should be included with the 4. So it should be the pin points that we measure. And functionally, we know that reaching backwards, that's a very important function for all of us, for self hygiene and also reaching back in the pocket and for dressing purposes. So I'm thankful to Fulcrum for doing the preliminary studies with the Phase II and open-label study to allow us to actually gain that insight, and I can say that going forward, we would be analyzing. So again, this is all relatively new, and we haven't had time to do a deeper dive and look into the fifth quadrant and how it changes over time. But I expect that it is also changing in accordance with the other quadrants. And with the Fulcrum's data that were presented, it actually includes a fifth quadrant. So the decline that you've seen and the improvement in overall total reachability, that actually includes the 4 plus the fifth quadrant data.

Got it. There are a few questions here on the enrollment criteria. So why don't I turn that over to Judy, if you want to talk a little bit about the enrollment criteria? And then the second part of that question I will ask of the [indiscernible] to answer.

Okay. So I'll just outline the enrollment criteria briefly. I think first and foremost, ReDUX4 trial was very successful for us, right? It helps us to understand statistical considerations, variability, drug effect, and it enables us to statistically power the REACH trial. So the inclusion exclusion criteria for REACH are very similar to the ReDUX4 trial. A couple of things to know, as we've already discussed, we have enriched this slightly in terms of ensuring that we will be enrolling patients who are most likely to show disease progression as measured by reachable workspace by defining sort of an upper and lower limit for inclusion. The age range is very standard for a drug in this point of development. I know many people are interested in having older ages included, also having younger ages included. Our current trial includes at least 90% of the representative population for FSHD, and we're very proud to be able to include that broad age range. In drug development, this is how you start with this age range. We continue to examine exposure questions, safety questions, efficacy questions. And we will continue to learn more about the drug and hopefully be able to increase the age ranges as the development program progresses. But as I said, at this point of development, 18 to 65 is very standard. And because this disorder is diagnosed in the second decade of life, that inclusion criteria does cover, as I said, over 90% of the population. So I don't know if there's anything additional in the question, Esther, that I haven't covered. But I think those are probably the most important criteria, along with perhaps one more, which is the inclusion of patients who have the diagnosis of FSHD 1 as well as patients who have the diagnosis of FSHD 2. And Dr. Johnson had -- it was in his comments that clinically, we can't tell the difference. There's up-screen genetics that are different to the clinical presentation in the clinic and the rate of progression are similar.

And the second part of that question, Dr. Johnson, perhaps you can take a stab at. Are there any natural or lifestyle factors which influence variability in this disease? And which could be used to narrow the inclusion criteria or stratify patients to get to a higher probability of success.

Unfortunately, there's not. There's been a number of things that have been looked at. And today there's no lifestyle factors that -- which specifically are known to change the rate of progression in FSHD. So I think I agree with all the ones that Fulcrum has selected in terms of the key inclusion/exclusion criteria to capture the right population.

Got it. And Dr. Han, this question, I think it's best for you. Since RWS focuses on upper extremity function, are there any data or correlation with RWS to demonstrate any improvement or stabilization in patient mobility.

I think it looks like Dr. Han might be offline. So perhaps we can talk about that question perhaps while he gets back online. There he is, perfect. So Jay, I don't know if you heard that last question about reachable workspace perhaps being able to detect issues with mobility.

Yes, I'm sorry, my connection was bad. I missed it. But I appreciate that. So we are working on that part and trying to develop another outcome measure for the lower extremity. And looking at the connection between the reachable workspace and the mobility in the lower extremity, I'm sure there is because as the disease progresses, yes, the upper shoulder girdle is affected. But there are patients who actually show earlier or sometimes even significant lower extremity weakness. And these are atypical, I would say, in a stereotypical way, the upper extremity and then the face, then it actually gradually moves down and involves lower extremity, especially the ankle dorsiflexion and the ability to sort of pick up your toes as you swing through with your gait, that kind of motion too. But I'm sure that is, but we haven't looked at that specifically.

Got it. here's another question on RWS, surprisingly, Dr. Han, I think this one's for you as well. What would be the biological or physiological rationale for why dominant and nondominant effects are slightly different with the RWS measures.

So these are all excellent questions. And I wonder about that, too. And within the field, I can tell you, historically, the clinicians, the giants of the field who've actually in the previous years and decades ago, who are very observing and monitor patients and how they present it clinically, they noticed that there were -- there seems to be some asymmetry in the dominant and nondominant side, yet some of the follow-up studies show that there wasn't. It was symmetrical. There weren't statistical difference. However, that was kind of a controversy within the field itself, whether there truly was a dominant and nondominant difference? Or was it something that people were just noticing anecdotally, case by case. But -- so we actually looked at that. And by reachable workspace being a quantitative and very sensitive measure now, I feel that there is a difference between dominant and nondominant side, reachability and reachable workspace in multiple studies now. It's not just one-off, but many, many studies, hundreds of patients' data, there's a dominant and nondominant difference and the progression, the rate in which the dominant side decline appears to be more rapid than nondominant side. And what -- why do I think that is happening. It's a good question. I wonder, however, how I rationalize, how I think about it is that it's a genetic disorder. All the muscles in your body are affected. You're born with it, and you're going to crawl when you're baby and then you're going to pick up the spoon and you're going to throw the ball, you're going to do a lot of things over the years, a lot more things with your right hand. And if you are right dominant, then your left side, your nondominant side or your left-handed dominant side. Anyway, you're going to be using the dominant side more than the nondominant side over years cumulatively. I mean, you think about that. And that's probably why the dominant side is affected more and declines at a rapid rate because there probably is some threshold, a point where the fiber fatty deposition in the muscle then becomes prominent and you start to lose functionality at a more rapid rate. So for me, I don't know that anyone in the world has a perfect answer or the right answer for you because that has not been studied and what the underlying pathophysiology and biomechanics is there. But that's how I kind of think about it together.

Got it. And Judy, this one is for you, tied to that. In the REACH trial, is RWS measured on both arms or only the dominant arm.

So we are only measuring it in the dominant arm as is conventional in a clinical trial, we choose a representative endpoint. And so we are allowing patients to identify whether it's dominant or not. We will report out to the primary variable on the dominant arm.

Thanks, Judy. On this next question, I'll throw it to you, Judy, and maybe Chris can jump in as well. Given the ReDUX4 data, how do you feel about magnitude of the benefit here and the clinical relevance of that?

Sure. Chris, I'll start and then ask you to jump in certainly. It's an important question. It's one that Jay has -- I'm sorry, that yes, the Jay has already started to elucidate. So what's interesting about our trial in terms of the reachable workspace is that you saw that the difference between drug and not drug was not limited by the effect of the drug. It was actually defined by the rate of progression. So I think the important thing to understand here is that the drug effect showed 0 change. And so when you're thinking about a clinical trial, understanding the clinical relevance of that rate of progression and the quantitation of reachable workspace is important. I think it was -- I believe it might have been Jay, who made this comment earlier, and it's something that we're doing in this clinical trial. One of our goals is to really help the community to understand the clinical relevance of the quantitation of reachable workspace. And we do that in a couple of different ways. The most important way that we have done it with the ReDUX4 data and REACH will be an important part of this is to look at the relationship, as I outlined, between reachable workspace and other important outcomes, like function and fat infiltration. And what does that relationship look like? What is the relationship between the Neuro-QoL and reachable workspace? What is the relationship between patient depression and the reachable workspace? So being able to anchor the changes in reachable workspace with those more qualitative, but they're perhaps more familiar endpoints using them as anchor points is going to allow us to be able to talk about reachable workspace through these anchors in ways that are easier for people not as sort of closely involved in the technical aspects of reachable workspace to understand. So we believe that there's clinical and statistical relevance, but what we'll continue to do is tell that story in a way that anchors those quantitative reliable changes due to the qualitative changes observed by Neuro-QoL by PGIC as well as the quantitation by MFI. Chris, I don't know if you have anything to add to that.

Yes. I would say, on top of that, Judy, we're obviously very well articulated is that we also think about the magnitude of effectiveness in terms of risk-benefit balance. And in this case, we already have over 3,600 people exposed to losmapimod in a variety of different conditions. We understand the safety data set well. There are no signals that we're concerned about at this point. And as Mel pointed out, this is remarkable for a rare disease drug to have this kind of safety data set going into a Phase III trial as we reviewed today and as Judy just articulated, the data so far inferred that the potential for positive benefit risk is high, and we've designed this trial in order to help further elucidate that with quantification of benefit and then further elucidation of the potential risks.

Great. Thank you, Chris. This next question is for Dr. Han. How sensitive is the Kinect setup as in does the Kinect device have to be set at the exact same length off the ground to provide consistent assessment across trial sites and patients.

Yes, that's a great question. So within the given brief limited time, I didn't go into all the details of the preliminary and all the empirical data that we did, I mean, like I told you before, we started this program to develop a quantitative granular sensor-based outcome measure, which was not in existence before. So when we started this 15 years ago, that's actually before iPhone and smartphone. I don't know if you guys can all appreciate that, remember, so we started this many, many years ago. We started with the stereo camera work. We started with the motion -- the full-on motion capture system. We tried different poses, we tried different height off the ground, the distance it needs to be. So that all -- a lot of work went into really developing a system and a program that's reliable and robust. Again, all that work already has been done. And the engineering and the software and the algorithm and the protocol has been validated and has gone through peer review in engineering science literature, and it's published and other people, groups have tried to recapitulate and reproduce and that's been found to be the case. So we feel that we have a very good system that's translatable and that's easy to apply in multiple studies, and that's been borne out with the previous Fulcrum studies. And currently, it's now really being up -- taken up by FSHD community around the world. And many, many sites are coming on board. They want the system to evaluate their patients clinically and also join clinical trial network. So all that work in terms of the specifics of how the system is set up, that's all been done previously. Obviously, I couldn't go into all the details of that, but that has been laid out in the previous literature and now in real-world situation, in clinical trials and preliminary studies, it has borne out to be robust.

Thank you, Dr. Han. Mel this next one is probably best for you. So oral administration is definitely ideal. But as other modalities eventually enter the clinic, how do you see the landscape changing? And is intrathecal administration a hurdle for this patient population?

Well, as I mentioned, FSHD is a debilitating malignance and very progressive disease. And as you can tell from the different positions we've spoken about how these patients disease manifests itself an oral small molecule therapy is the best option. When we ask patients what they want, they want a oral small molecule. As patients' disease progresses, using any type of injectable device of any nature becomes a little bit more complicated. So we feel, as we go forward, we're launching with potentially the most optimal pharma therapy, and we'll wait to see what -- how the market evolves, but we think that an oral small molecule is the best option for patients.

Thanks, Mel. I have a few questions here on the trial design. So I'll ask you two, and Chris, feel free to jump in. What was the thought process or justification for randomizing on a one-to-one?

That's a great question. And it's kind of fun to think about the thought process that went behind our methodology and how we got there. So a couple of things to put this into context. One is, this is probably the first interventional therapy trial that regulators are going to see. So although there are a lot of statistical considerations that we could take, there's a couple of things that we needed to do in this trial. One is to continue to understand disease progression off of drug. As I mentioned earlier, the difference between drug and nondrug in our hands with losmapimod is actually defined by the placebo arm. So when we are articulating a difference, it is really the natural progression of the disease that's defining that. We wanted to have as many patients as possible represented in that natural course of disease. Secondly, we've had a lot of questions about reachable workspace today. One of the ways that I talked about earlier is that to help people understand the clinical relevance behind these quantitative changes is to do these statistical comparisons between Neuro-QoL and reachable workspace, Jay showed that there's a very high correlation. We want to continue to demonstrate that. We'll look at those anchors on qualitative and quantitative measures and to best do that a one-to-one randomization scheme. It's really well-suited. It's the best way for us to be able to meet those goals of really helping people to understand disease progression in the absence of drug, but also to provide a data set that helps us to articulate the benefit of reachable workspace as anchored by other things. And then Chris made a very important point earlier, which is to continue to understand the safety of the drug and do that by comparing to placebo.

Great. Thank you, Judy. This is the last question. We're nearly out of time here, and then I'll turn it over to Bryan to wrap up. Judy or Chris, feel free to answer. Is there any plan to enroll patients in another study, pediatric patients in another study. And then the second part of the question is, will there be an open label extension for this Phase III?

Chris, do you want to go ahead and take that?

Yes. Sure. So we're obviously encouraged by what we're seeing so far that's been predominantly in adults. And we understand the huge need that goes into the pediatric population. There are kids who are diagnosed with the disease certainly less than 18, even younger. And they have a slightly different course. They have slightly different manifestations of the disease. We still have some work to do to understand what would precisely be the best measurement of function in the pediatric population. We don't yet know whether RWS as we're assessing it here, is the most appropriate endpoint. So we're doing that work. We're thinking deeply about it. We're talking with physicians and scientists from all over the world to help understand this a bit better. We've heard very clearly from the patient community how much of a need this is, how much urgency there is, and we feel that urgency and we'll strive to meet that particular need. In terms of open label, there will be an open-label extension that will be associated with this trial. More details about that will be coming out as the plans are further elucidated, but our intent is to ensure that we have longer-term access and longer-term data collection from people who do participate in the REACH trial.

Thank you, Chris. And thank you to all the analysts. I'll turn it over to Bryan for wrapping up.

Yes. Again, thanks so much for everybody dialing in today. Again, we are very appreciative of the severity of this disease. This is 500,000 people living with FSHD worldwide, plus their families and their caregivers. And we are very pleased to be able to be moving forward here to be able to leverage the successful data that we generated in the Phase IIb trial, the impact that it had on patients in only 48 weeks with only 80 subjects, and we're very pleased to get that alignment with regulators to be able to do that. So we're extremely excited about this. We think it's a tremendous opportunity to fill a very meaningful unmet need. And we appreciate everybody's time and everybody's continued engagement. Thank you.