Sorry, there's a disconnect between the three slides. Oh, okay. I'll just follow this one. Second of our program that's in clinical development is FTX-6058, which has best-in-class potential for the treatment of sickle cell disease by elevation of fetal hemoglobin. As I mentioned, these are outputs of our product engine, which have activities in blood disorders as well as muscle disorders. This is Sean. Sean is representative of the 33,000 people in the U.S. who have FSHD or facioscapulohumeral disease. He's also representative of the approximately 22% of those people who will end up in a wheelchair despite leading expecting a normal lifespan. We've already obtained Fast Track designation for losmapimod as well as Orphan Drug Designation. This really speaks to the significant unmet medical need that this population represents. There is no available therapy for these patients. It also impacts the whole family. Sean's son, Patrick, is Sean's primary caregiver, and that's typical for this disease, as the course of the disease means the family has to help facilitate and look after the patients. The disease gets its name from the typical presentation. It begins in the face, facio. An inability to purse the lips, to drink from a straw, blow up balloons, those kinds of things. A very stoic look because muscles that enable each of us to smile and express emotion are dystrophic. It then progresses into the shoulder, hence the name scapula, so facioscapular, then into the trunk of the body, humeral dystrophy. 95% of the patients report that the loss of ability to move the shoulder is the primary debilitating aspect of the disease. I would ask each of you to consider getting up in the morning, not being able to brush your hair, not being able to brush your teeth, not being able to put on makeup, having to ask someone to get the coffee cup down for you. The entire family adapts to this disease. Two-thirds of the patients are genetic, are inherited, so it's a genetically defined disease that is passed from parent to child. That enables us, once we identify a patient with FSHD, to immediately identify other patients that are in the family that may also be suffering from this disease. As I mentioned, it progresses from the face to the shoulder, and the primary disease aspect that patients find most disconcerting is the inability to lift their hands above their shoulder. This is. Because of this, we have implemented innovative clinical outcome measures using an instrument called Reachable Workspace. In essence, Reachable Workspace takes advantage of a Kinect video camera to track the patient's ability to lift their arm above their shoulder on the ipsilateral or contralateral side or below the shoulder on the ipsilateral and contralateral side. That provides a sensitive and accurate measurement of the Reachable Work Area that these patients experience. A patient with FSHD is unable to access those regions above their shoulder. We can use this as a measure of disease progression. In addition, we are assessing muscle fat infiltrate. As the muscle dies, fat infiltrates the muscle, replaces the protein in the muscle with fat, and we can assess this measure of muscle health using MRI modalities. We initiated the phase III program. results we obtained from a phase II program where losmapimod just demonstrated stability of disease and improvement in Reachable Workspace compared to placebo after a 48-week treatment. In this slide, on the left-hand side shows the Reachable Workspace on the dominant side. I'm right-handed, so that would be my dominant side or the non-dominant side. In orange, it's showing the losmapimod-treated patients with stable disease over this 48-week period, and the placebo-treated patients in which the Reachable Workspace has deteriorated by about 4% or 5% over that roughly 1-year course of treatment. In a patient voice of the patient survey that we did in collaboration with the FSHD Society, patients reported that for them, stabilizing disease and for their families, stabilizing disease would be a significant advance for them. There's no fit therapy. They've learned to adapt to the disease, and if they get... Their vision and wish is to stay where they are in the disease progression. Of course, improvement would be wonderful, but stabilization is acceptable as well for these patients. Having the 48-week data, we continued to look for an additional 48 weeks, and this shows the 96-week results. In that study, patients that were on placebo or on losmapimod all crossed over in an open label fashion to receive losmapimod. 95% of the patients chose to continue in that study, speaking to the very robust safety profile that we've seen with losmapimod. The orange line on the left-hand side shows the Reachable Surface Area stabilized over the course of the 96 weeks of treatment. The blue dashed line shows the deterioration in Reachable Workspace, dominant side on the left, non-dominant side on the right. The deterioration in the Reachable Workspace over the first 48 weeks that I showed you previously. The orange dashed line shows those patients who crossed over from placebo onto active drug, onto losmapimod. Again, you see stabilization of the Reachable Workspace as over the subsequent 48 weeks of receiving treatment. This was seen on both the left, the dominant side, as well as the non-dominant side. Sorry. Our phase III trial enrollment is ongoing. We plan to complete enrollment in this phase III trial, called the REACH trial, in the second half of 2023. Our other clinical program that has advanced in the last year is our program of FTX-6058 for the potential treatment of sickle cell disease. FTX-6058 also has Fast Track designation and also has Orphan Pediatric Designation. Again, speaking to the significant need for new therapies in sickle cell disease. Part of our interest in elevating fetal hemoglobin for the, or HbF for the potential treatment of sickle cell disease comes from human genetics. On the left-hand side of this depiction shows the sequelae in, of patients who have sickle cell gene and sickle cell disease. They experience potential for stroke, acute chest syndrome, nephropathy, osteonecrosis, ulcers, and pains. There are patients who have a, an additional genetic alteration in which they continue to make HbF. Each of us make HbF until we're about 2 or 3 years of age, and then adult hemoglobin takes over, and that's when the sickle cell mutation begins to affect these patients. In these individuals who have both a persistence of fetal hemoglobin, so-called hereditary persistence of fetal hemoglobin, they do not shut off this fetal hemoglobin. As the fetal hemoglobin rises, they have an amelioration of their symptoms. 5%-10%, they have reduced morbidity and mortality, reduced recurring events as they get to 20% fetal hemoglobin, and essentially asymptomatic presentation at 30% HbF. The goal of the program was to elevate HbF with an oral small molecule agent. We have been able to do that with FTX-6058. It has the potentially best in class therapy as it will be working, as I'll show you, works in combination with hydroxyurea or alone to elevate fetal hemoglobin in a convenient oral formulation and has the potential therefore to be physiologically modifying. We are in the midst of a phase Ib clinical trial in sickle cell patients that are aged 18-65, either on or off hydroxyurea. There are currently ongoing, either completed or ongoing, 3 dose cohorts in this trial. Cohort 1 received 6 milligrams for a 4-week period, followed by an 8-week treatment extension. Cohort 2 received 2 milligrams, followed by an 8-week treatment extension. We have completed the 8-milligram Cohort 1 and are completing this, the site Cohort 2 currently. We have just initiated Cohort 3, which is the 12-milligram cohort. Again, following the same 4 weeks of treatment, followed by an 8-week treatment extension. As is normal in a phase I trial, the primary endpoint of this trial is safety and tolerability along with pharmacokinetic measurements. Secondary endpoints, among others that I'll show you today, are the change from baseline in HbF and the change from baseline in a measure of red cell health and vitality reticulocytes. We've also explored a number of exploratory endpoints, and I'll show you some of the biomarkers of hemolysis that we have observed. In this phase Ib study, we have 2 subjects treated at 2 milligrams and 10 subjects at 6 milligrams. These subjects overall had a mean baseline HbF of 8.4%, and 3 of them that were receiving 6 milligrams were also on hydroxyurea. One of the goals of this study was to understand the potential of FTX-6058 in combination with hydroxyurea. Overall, FTX-6058 was well tolerated. There were 14 Treatment-Emergent Adverse Events, 2 of them possibly related to study drug. One was a headache, one was lip numbness. These both resolved on continued treatment with the drug. They were of mild severity and considered non-serious. There were 2 treatment emergent adverse events that were characterized as vaso-occlusive crises. They were characterized by the attending physician as unrelated to study drug. One was reported as an SAE with acute chest syndrome. This was in a subject that was non-adherent. There were no lab-related adverse events and no discontinuations due to the TEAEs. This shows the totality of the treatments and as well as the treatment periods for 12 patients. Patients 1 through 10 received 6 milligrams. Patients 11 and 12 received 2 milligrams. One of the issues that we faced early on in this program was confirming compliance and that the patients were actually taking the drug. We were able to confirm compliance in 2 different ways, by pharmacokinetic measurements, actually measuring drug levels. Also by pill count, that is, did they return how many pills did they actually return? By that analysis, patients 4, 5, and 6 actually did not receive any treatment. We have not included those patients in on-treatment analysis. Other patients, we were able to confirm treatment for the indicated number of days, be it 28 in the case days in the case of subjects 9 and 10, or 84 days in the case of subjects 7 and 8. The 2-milligram dose, the 2 patients 11 and 12 are ongoing currently. While patients 4 and 5 were noncompliant, we were able to observe some data from these patients and subject 5 on the left-hand side, this was the non-adherent patient, you see the stable protein levels of HbF and the stable message levels over the approximately 96 days of treatment. On the right-hand side is subject 4, who is noncompliant for the first roughly 50 days of treatment. As we switched to observed dosing and we confirmed they were taking drug, we began to see the anticipated increase in HbF and the anticipated increase in messenger RNA. If we look now at all of the compliant patients, the 2 milligram, which is ongoing on the right, and the 6 milligram ongoing on the left, what we observed is that there was a consistent and not uniform rate of increase in fetal hemoglobin. On the top left is shown the absolute% HbF levels. On the bottom is shown the normalized levels. Every patient responded. Patients 7, 9, and 10, as indicated by the asterisks, were on hydroxyurea. They showed a comparable rate of increase as patients off hydroxyurea. We also observed a dose-response relationship in that 2 milligram appears to be a minimally effective good dose. 6 milligrams appears to be a clinically effective dose. The other thing I'll draw your attention to is the decline in HbF following termination of the drug. As expected, HbF rose with this oral treatment. When the oral treatment was discontinued, HbF levels fell, consistent with the pharmacology of the agent. Just to illustrate the effect with hydroxyurea, on the left-hand side shows the subject 7 who is on hydroxyurea starting at about 10% HbF. On the right, subject 8 started at about 10% HbF, although they were not on hydroxyurea. You see a similar rate and extent of HbF increase on or off hydroxyurea. We also wanted to look at biomarkers of hemolysis. That is, by elevating HbF, were we having a positive clinical benefit in these patients? We looked at that in a number of different ways. First of all, we looked at red cell distribution with sickled red cells have a broader distribution. As the HbF rose, what we can see is that the red cell distribution width returns to normal, the dashed horizontal line. Once drug is discontinued, indicated by the vertical dashed line, red cell distribution width begins to increase again. Indicating the onset of the effect of the drug and the washout of the drug as it cleared. Total bilirubin fell, indicating a stability of the red cells. Absolute reticulocyte count went down again by about 50%, an anticipated effect of prolonging the life of red cells as we elevated the HbF. Total hemoglobin rose by about 1 gram per deciliter, again, indicating that anemia was being mitigated, hemolysis was being positively impacted, and the patients appeared to show the beginning of clinical benefit with this elevation of HbF. As we look forward to 2023 in this program, we anticipate completing the phase Ib study. We have amended the protocol and increased the number of sites really to reduce the patient burden. During the pharmacokinetic studies required, patients come in for about a day and a half to receive multiple blood draws 3 times during the course of treatment. We've learned that FTX-6058 is a very well-behaved molecule, and we've obtained the necessary pharmacokinetic data that we wanted in that program. By amending the protocol, increasing the number of sites, we anticipate this will accelerate the enrollment as we look forward to enrolling up to 10 patients at 12 milligrams through the course of 2023. That data in combination with the refined PK/PD model puts us in a good position to select our final dose for the pivotal trial. We expect selecting that final dose before the end of 2023 as well. As we look forward to the future of Fulcrum, we have a diversified pipeline of clinical assets, both representing potential significant benefit to patients with muscular dystrophy or sickle cell disease. We anticipate completing enrollment of the REACH phase III study this year, completing the phase Ib and selecting the registrational dose by the end of this year. We anticipate both of these compounds moving forward to be either first to market or best in market class. Our cash runway through late 2024 positions us well to deliver on these goals. I'm excited for the potential we have to bring benefit to the patients with these genetically defined diseases, improve the lives of them and their family, and I thank you for your kind attention. Thank you so much, Robert, for running through that presentation. A couple questions for you. Can you talk a little bit more about what motivated you to start the company, what your vision was at the time, you know, how things have evolved, now, you know, what excites you about Fulcrum today and brought you back from your board role into a more operating-focused role? Thank you for that because my enthusiasm for Fulcrum over the last seven years has only grown with the potential of using small molecules to treat gene therapy. When we started the company seven years ago, actually FSHD and sickle cell were two of the first three programs that we initiated the company with the vision of could we turn off a disease-causing gene called DUX4 and treat muscular dystrophy? Could we turn on fetal hemoglobin and treat sickle cell disease? What I'm most excited about is not only the progress and the wonderful team that has enabled that progress over the last seven years, but we are finally in the place where patients have the potential to see benefit from that, and that's really what brought me back. I have been doing drug discovery for many, many years now, 30-plus years, and to be able to see the potential of improving the lives of patients and their families with these agents is really what motivates me. That's awesome. Are you able to share anything about the ongoing CEO search? Like, how long are you willing to stay on as interim CEO? I'm gonna be interim CEO as long as it takes to find the next person to lead Fulcrum into the next stage of growth. We've just initiated that search, so it's very early, but I'm committed to the company and the future of the company. Awesome. Thank you. Esther, a couple of questions for you. I know you had it up on the slide, but can you remind us a little bit about your runway guidance and talk a little bit about what this will help deliver? Sure. As Robert mentioned, our runway is through late 2024, and that helps us that gets us to completing our phase Ib for the sickle program and being prepared to get into a phase III for that program. We're also going to complete enrollment in our FSHD phase III trial, and it's a 48-week trial, so potentially be in a position to deliver data with that as well. How do you think about business development and strategic partnerships? Sure. Business development has always been an important part of our strategy. If you know, look in our past, we have leveraged business development for non-dilutive sources of financing. We've done early-stage discovery partnerships. Now as we have two clinical stage assets, we will be looking at all opportunities to deliver value. you know, I know you have a little bit of it on the slide, but are there any other key catalysts for this year? No. This year, we just released data on FTX-6058, and that, you know, it's been an exciting couple of weeks for us. Our most important catalyst will be completing the trial for FSHD. The most important, in my view, is the FTX-6058 data readout from the phase Ib at the end of the year in the fourth quarter. Awesome. Thank you. Maybe we dive in a little bit into the science information. Santiago, why was RWS chosen as a primary endpoint for FSHD? Was there anything else that you considered? There are many endpoints that you could use in FSHD. It's a muscular dystrophy, and many endpoints have been used in muscular dystrophies in the past. What was attractive about that endpoint is that it has a very good test-retest reliability, and it also can measure small differences in patient outcome. Especially if you think about this disease that is a very slowly progressive disease, it's important to have an instrument that is good enough to detect those changes without having to extend a trial for five years or more, which will be undoable. Can you characterize what a good dataset should look like from the REACH trial to obtain approval? Well, if you see our phase II data, our phase II data actually was already pretty compelling. We hit three endpoints, all of them of clinical relevance, both in the Reachable Workspace, MRI changes with reducing reduction on the fat infiltration. The fat infiltration is the hallmark for this disorder, and then a Patient Global Impression of Change. All of these endpoints were positive in phase II. Our phase III design is very similar to the phase II. Same duration, approximately the same patient population. It's just a bigger trial, more patients. We think that we have a robust p hase II that will support our phase III success. How is enrollment going for the trial? We're doing well. We are aiming to enroll the study this year. The truth is that patients are waiting. There is nothing else for these patients. There is no therapy available, and they have been waiting for something. It's actually more the ability and the capability of the size to be able to, you know, get the patients in than the patients. The patients are there waiting for to be enrolled. Thank you. Then switching gears a little bit to talk about SCD, can you discuss the differences in responses between the HU and non-HU patients in the six-milligram cohort? Yeah. We saw three patients on the six-milligram cohort that were treated with HU. We didn't see any differences in either efficacy or tolerability. The effect seems to be additive, and that's what we were actually expecting. In the next cohort, 12 milligrams, we will accept patients either with HU or without HU. Can you explain a little bit the two VOCs? Like, did these occur while patients were on the drug? And if so, was this in line with pretrial history of VOCs for these patients? These patients had a baseline. I mean, in the previous year they had a number of VOC. It was not unexpected to have VOCs. One of them, as Robert mentioned, was not adhering to the drug when she had the VOC. She started to be not adhering on day 28, 29, and the VOC was on day 36. The patient was admitted in the hospital for 3 days. We know that the patient was not adhering because she was not doing the observed dosing. The other patient is very different. The other patient had the VOC about 60 days into the study. That patient had a good response. He had gone up about 4.5%-5% response in HbF. It's a different type of situation. This patient plays soccer because he knows that he gets dehydrated when he plays soccer, he goes to the emergency room before an important soccer game and gets hydrated and gets anti-inflammatory drugs, and then he goes and plays soccer. He does that kind of prophylactically. In any case, he went to the emergency room. We have evidence that he went to emergency room. He said that he had a VOC. A VOC that is considered unrelated to the drug was logged. Thank you. Then, you know, what is your therapeutic goal for HbF induction for the drug? I think previous scientific leadership had characterized 5%-10% as the goal. What is your view, and do you think there's room for higher levels of induction? Yeah. At 6 milligrams, we are already seeing a good level of HbF induction. You know, the max HbF that was seen was nine and a half, so kind of we are there. I think that there is potential for more HbF, and that's what we are going to be exploring with 12 milligrams. If you recall, we presented a few months ago the healthy volunteer data. We saw dose response in MRNA in those patients, in those subjects up to 20, 30 milligrams. We could potentially go a little bit higher and see what will be the efficacy. Right now we are already in that 5 to 10. Talking a little bit about that 12-milligram dose cohort, how long do you think it will take to complete enrollment, and what would you need to see in order to determine whether a higher dosage would be needed? We are pretty comfortable with what we believe it will be the enrollment from here onwards. We, as Robert was saying, we are simplifying the protocol that was very difficult for patients, and we are also increasing the number of sites. Enrollment should go much better. We have a lot of freedom to operate within this protocol in relationship of the number of patients, which is up to 10 in each cohort and the ultimate dose that right now we could go up to 20 without any protocol amendment. We have a lot of flexibility. Speaking on protocol amendment, can you share a little additional color on any amendments that may improve adherence and increase enrollment rates? Yeah. I think, you know, Robert was mentioning it. We were doing a very intensive PK, a lot of blood draws during the study. We are eliminating a lot of it. Not all of it, but a lot of it. That will make life much easier for patients, much easier for the sites, and adhering much easier. The other thing is that, you know, I think that we have data right now that is pretty compelling, at least in my view, is pretty compelling. I think that sharing that with investigators is going to be important and ensuring that they know what this drug can bring to the patients. I think it's going to be easier because now there is data. What are your plans on regulatory interactions for registrational trial now that you have Fast Track designation for this program? Yeah. We haven't talked about what are our concrete plans. Obviously, you know, we are aiming to start phase III next year, the following year. And we are aiming and we are guiding towards, having a, phase III dose selected during this year. In the meantime, you know, it's, it's really possible that we'll have interactions with the FDA. You know, can you share any thoughts on the phase III trial design? Will you use HbF as a surrogate marker for approval? We haven't really started to think about what will be the phase III design. There are many potential endpoints that other people have used, from VOCs and hemoglobin on HbF. Again, it's still a little bit early to talk about that. All right. Well, a wealth of information. With that, perhaps if there are any questions in the audience? All right. Well, thank you guys so much for your time and for the presentation. It was enlightening. Thank you. Thank you. Thank you. Thank you.