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spk05: Good morning and welcome to the Fulcrum Therapeutics Third Quarter 2021 Conference Call. Currently, all participants are in a listen-only mode. There will be a question and answer session at the end of this call. I would now like to turn the call over to Ms. Naomi Aoki, Senior Vice President of Corporate Communications and Investor Relations at Fulcrum. Ma'am, please proceed.
spk00: Thank you, Henry. Good morning and welcome to the Fulcrum Therapeutics Conference Call. Please be reminded that remarks made during this call may contain 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 timelines, 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 an obligation to do so. please refer to our most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with our business. With me on today's call are Brian Stewart, President and Chief Executive Officer, Chris Morabito, Chief Medical Officer, and Peter Thompson, Vice President of Finance and Accounting. Judy Dunn, our President of R&D, and Paul Bruno, our Senior Director of Corporate Development, will also be available for Q&A. Let me run quickly through this morning's agenda. Brian will begin the call with a corporate overview and key updates. Chris Morabito will review our programs in sickle cell disease and FFHD. Peter will cover our financials, and then Brian will open the call for Q&A. With that, it's my pleasure to turn the call over to Brian.
spk03: Thank you, Naomi. Good morning, everyone, and thank you for joining us today. 2021 has been a remarkable year for Fulcrum, and we continue to make great strides in the third quarter across our pipeline, our product engine, our business, bringing us closer to our mission of delivering life-changing medicines to people with rare genetic diseases. This past quarter was particularly notable for the compelling clinical data we reported on FTX6058, our oral HBF inducer for sickle cell disease and other hemoglobinopathy. In August, we reported results from our ongoing phase one trial in healthy adult volunteers. As many of you know, the current treatment landscape in sickle cell disease consists of therapies that only target select symptoms. Human genetics clearly demonstrate that by inducing fetal hemoglobin, or HBF, that HBF treats the root cause of sickle cell disease. And by inducing HBF, we believe FTX 6058 has the potential to address the broad range of symptoms of sickle cell disease, providing a functional cure with an oral therapy. As you'll hear from Chris Morabito later on, we are excited about the results from this trial, both in terms of the tolerability profile and the robust induction of HBG mRNA, which has been highly correlated in our preclinical studies with HBF induction. Looking ahead, we remain on track to provide an update from our ongoing Phase I trial by year end, including data from our 20 and 30 milligram dose cohorts and healthy volunteers. At that time, we also plan to share new data, further elucidating the relationship between EED inhibition via FTX 6058 and HBG mRNA expression. Meanwhile, we are moving quickly to initiate our Phase 1b trial in people living with sickle cell disease and are on track to begin enrolling patients by the end of the year. We also plan to submit an IND for FTX6058 by year-end in additional hemoglobinopathies, including beta thalassemia. Now let's turn to Los Matamod, our candidate for FSHD. FSHD is the second most prevalent form of muscular dystrophy. There are currently no approved drugs and nothing else in the clinic for this devastating disease. People with FSHD are typically diagnosed in their late teens or early 20s. As fat progressively infiltrates their muscles, people with FSHD lose strength, function, and independence. There is an urgent need for a drug that can slow or stop disease progression. The data we reported earlier this year from our Phase IIb Redux IV trial highlights LosMapimod's potential to do just that, demonstrating delayed progression and even improvement across a number of measures of muscle health, function, and patient-reported outcomes. We remain on track to meet with regulators before the end of this year and look forward to providing an update on those discussions in the first quarter of 2022. Turning to FulcrumSeq, our product engine and innovation backbone of the company. FTX 6058 and LosMapimod, as well as our ongoing collaborations with Acceleron and Myocardia, are a testament to the power of FulcrumSeq. which has allowed us to rapidly identify novel, high-quality targets that modulate the root cause of genetically defined rare diseases. Notably, in addition to our IND in hemoglobinopathies, we expect to submit an additional IND by the first quarter of 2023. We have also made tremendous advancements with FulcrumSeq to enable our drug discovery efforts at what we believe is an unprecedented scale in disease-relevant settings positioning us to dramatically increase the pace of discovery. As we shared this morning, Chris Moxham, our chief scientific officer, will be leaving Fulcrum to pursue new opportunities. We are grateful for his contributions and wish him the best in the next chapter of his career. During this transition, the discovery organization will continue to report into Judy Dunn, our president of R&D. With her leadership and strong organization already in place, we're well positioned to execute against our discovery goals. Finally, we continue to build out our leadership team this quarter with the appointments of Mel Hayes as our Chief Commercial Officer, Mani Sundaranjan as our Senior Vice President of Technical Operations, and Naomi Aoki as our Senior Vice President of Corporate Communications and Investor Relations. These newly created roles help us build out our downstream capabilities and further strengthen our team as we move closer towards becoming a commercial organization. Fulcrum is in a tremendous position as we look to build a leading rare disease company. We are advancing two potentially life-changing therapies in clinical development, progressing additional early-stage programs, scaling up our discovery efforts, and building downstream capabilities, all on a strong financial foundation with a cash runway that now takes us into 2024. With that, I'd like to turn the call over to Chris Morabito. Chris?
spk12: Thanks, Brian. I'll first start with FTX6058, our oral HBF inducer. As Brian mentioned, we're extremely encouraged by the results we've reported in August, which suggests that FTX6058 could be a transformative therapy for people with sickle cell disease. Sickle cell disease affects an estimated 100,000 people in the U.S. and millions more worldwide. In people with sickle cell disease, a mutation in hemoglobin causes red blood cells to take on a characteristic sickle shape. These red blood cells often die prematurely, which causes anemia. The sickle-shaped cells may also damage blood vessels and restrict blood flow, causing vaso-occlusive crises, or VOCs, which appear as episodes of extreme pain and can manifest as stroke, acute chest syndrome, and other forms of organ injury. Together, these complications significantly impact lifespan, underscoring the tremendous need for treatments that address the root cause of disease. As an oral HBF inducer, FTX6058 has the potential to redefine the treatment paradigm. The link between HBF induction and improved outcomes in sickle cell disease is very well established, with both genetic and clinical data showing that increased HBF reduces or eliminates anemia, BOCs, and other symptoms of the disease. People who carry the sickle cell mutation and also have persistence of fetal hemoglobin present with much milder disease and have far better clinical outcomes. Typically, people with sickle cell disease have about 5% to 10% HBF, and we know from those with persistence of fetal hemoglobin that any increase in HBF beyond this has a positive impact on clinical outcomes. We believe an oral drug that induces HBF by two to three-fold from baseline would be life-changing for people with sickle cell disease, with potential to decrease both anemia and VOC-driven symptomatology. Preclinically, FTX6058 has been shown to induce HPF by two to three-fold in a wide variety of wild type and disease models, and the interim clinical trial results we reported in August show those preclinical data starting to translate clinically. The data demonstrated proof of biology and mechanism, as evidenced by dose-proportional induction in HBG mRNA, up to a mean 4.5-fold increase in the 10-milligram dose cohort. Our preclinical studies consistently demonstrate that increases in HBG mRNA and HBF protein are highly correlated.
spk11: Based on these results, we are aggressively moving ahead with this program. We have added a cohort of people with sickle cell disease to the ongoing Phase I trial.
spk12: The addition of this cohort helps us make our PK-PB model more robust, more quickly, and will further inform additional doses in the Phase Ib study. Dosing for this cohort will be 14 days at six milligrams once daily. In terms of next steps for the program, we anticipate sharing results of the 20 to 30 and 30 milligram cohorts of the ongoing phase one trial before the end of the year, as well as data to shed light on the intermediary steps linking EED inhibition via FTX6058 to induction of HPG mRNA expression. As a reminder, The aim of the Phase I is to evaluate safety, tolerability, and pharmacokinetics of FTX6058. The trial has also been collecting pharmacodynamic data to assess target engagement and HBG mRNA levels. Additionally, we are on track to begin enrolling people with sickle cell disease in the Phase Ib clinical trial before the end of this year. This multiple-dose Phase Ib open-label trial will start with a 6-milligram dose, and include a treatment period of up to three months with about 10 patients per cohort. The study is designed to confirm and build on our current results with the aim of demonstrating early proof of concept in sickle cell disease. We anticipate providing initial data from the Phase 1B trial in the second quarter of 2022. Following proof of concept in the Phase 1B, we anticipate moving into a potentially pivotal Phase 2-3 clinical trial in 2023. As we look at the existing and emerging treatment landscape for sickle cell disease, we see a tremendous opportunity for FTX6058. Only HPF induction has been demonstrated to broadly ameliorate symptoms of the disease. Approved therapies show modest benefit and only target certain symptoms. Other oral or IV programs in clinical development aim either to increase total hemoglobin or to reduce VOCs. Clinical studies have shown that increasing total hemoglobin S alone has limited impact on symptoms. Similarly, drugs that may reduce the rate of VOCs have minimal to no impact on anemia. Gene editing approaches, which share the same therapeutic rationale as FTX 6058, have shown promising results across the broad spectrum of symptoms, but come with an extremely challenging treatment burden for patients and families. We believe that an oral, once-daily medicine that can reduce or eliminate anemia, BOCs, stroke, and other symptoms, essentially providing a functional cure, will define a new treatment standard for sickle cell disease. We also believe FDX6058 could be transformative therapy for other hemoglobinopathies, such as beta thalassemia. The clinical results to date support initiating a trial in this patient population. And as Brian mentioned, we intend to submit an IND by the end of this year. Now let's turn to losmapamod, a potentially life-changing therapy for FSHD. As many of you know, losmapamod targets the aberrant expression of DEX4, the genetic root cause of FSHD. This aberrant expression causes muscle fat infiltration, which leads to degeneration and muscular dystrophy, and relentless progressive loss of function. We consistently hear from patients that their number one concern and number one objective in a new therapeutic is to slow or stop disease progression in order to preserve the function they have. REDUPS-4 is the most comprehensive therapeutic trial in FSHD to date, 48 weeks, comparing losmepamide 50 milligrams twice daily to placebo. In REDUPS-4, we saw clinically meaningful impacts on muscle structure, function, and patient-reported outcomes. On MRI, we showed a slowing of muscle fat infiltration in patients treated with losmepamide compared to placebo, which speaks to preservation of muscle structure. Patients treated with osmepamide also demonstrated improvement in shoulder strength, a key muscle group impacted by the disease. Importantly, we saw preservation of function measured by reachable workspace and trends towards improvement in timed up and go, which is an assessment of lower extremity function. With reachable workspace, osmepamide treatment resulted in improvements from baseline and reachable surface area in key areas, that impact activity of daily living and maintenance of independence, including reaching above the shoulders and behind the back. And finally, study participants on drugs reported feeling better compared to participants on placebo at the end of the 48-week treatment period. Lesmaphimod also has a well-established safety and tolerability profile. Approximately 3,600 patients have been exposed to Lesmaphimod across multiple indications, and the safety profile remains favorable. especially for severe and progressive disease for which there are no therapies. In terms of next steps, as Brian mentioned, we plan to talk with regulators before the end of the year, and we will be providing an update on those interactions in the first quarter of 2022. We're currently planning for a Phase 3 trial, which is our base case scenario. We gained significant insights from Redux 4 about meaningful and measurable clinical endpoints that showed sensitivity to disease progression and drug effects, and we are applying those insights to inform the design of a trial with the aim of expeditiously delivering the first disease-modifying drug for people with FSHD. On behalf of Fulcrum, I want to express our deep appreciation to the sickle cell disease and FSHD communities for their insights, their guidance, and their support as we work towards our shared goal of developing much-needed therapies for these difficult diseases. With that, I'll turn it over to Peter.
spk08: Thanks, Chris. Following our successful August financing, we ended the third quarter with $240.3 million in cash, cash equivalents, and marketable securities. Based on our current plans and projections, we expect this will support our operations into 2024. Collaboration revenue for the third quarter of 2021 was $4.9 million, compared to $1.8 million of collaboration revenue recognized during the third quarter of 2020. Research and development expenses for the third quarter of 2021 were $17.1 million compared to $15.6 million in the third quarter of 2020. General and administrative expenses for the third quarter of 2021 were $8.6 million as compared to $5.3 million for the third quarter of 2020. And our net loss was $20.7 million for the third quarter of 2021 compared to a net loss of $19 million for the third quarter of 2020. With that, I'll turn it back to Brian. Brian?
spk03: Thanks, Peter. As you've heard today, it's been a tremendous year for Fulcrum so far, and we are continuing to build on that momentum. We're very excited about the prospects for our programs in FSHD and sickle cell disease, two diseases with great unmet need where we have shown very compelling data to date. And we look forward to opportunities ahead to develop therapies to benefit patients with these and other rare genetic diseases. Operator, you may now open the line for questions.
spk05: Thank you. As a reminder, in order to ask questions, press TARD and the number one on your telephone keypad. Your first question comes from Dagan Ha of Stifel. Your line is now open.
spk06: Hi, good morning, guys. Thanks for taking the question. I guess I wanted to just kind of go back to the teaser for the additional data with regards to ED inhibition and HBGM RNA. I guess, can you maybe talk a little bit about what we can expect there? Is this mostly in vitro or in vivo? And will this cover transcriptomic analyses or proteomic analysis or something else? And then I've got a follow-up. Thank you.
spk03: Yeah, thanks, Dagon, for the question. So we haven't shared... More detail yet, I think one of the things that we've been doing and that we've spoken about is doing work to try to better elucidate that relationship between EED inhibition via FTX6050AID and this HBG mRNA increase that we've observed so far clinically, and obviously the protein increases that we've involved preclinically. So we anticipate that we'll be able to share that work along with the data update towards the end of the year, and we're excited to share more details on that.
spk06: Great. Thank you for that. And then the follow-up is with regards to your 30 milligram cohort data, I was wondering if you can maybe walk us through kind of the thought process after you kind of saw the 2, 6, and 10, recognizing 20 milligram was coming down the pike. What was sort of the driving factor that led you to 30 milligram cohort, and what exactly were you trying to divulge from that cohort data? Thanks so much.
spk12: Hi, Dagon. This is Chris. Yeah, so as you imply, we were very pleased with the data that we reported back in August. By up through 10 milligrams, we already demonstrated that we have a profile that looks like it could achieve our target, which is at least a two to three-fold induction.
spk04: Operator, can you put that line on mute?
spk12: So, we were pleased to see data that implied that we could hit our guideposts, our goalposts of two- to three-fold induction already. And based on what we saw, we made some good decisions, critical decisions about this program, including initiation of the Phase 1b study and going into beta thalassemia and other hemoglobinopathies. We haven't seen anything so far that makes us concerned about the profile, but we have taken the opportunity in Phase 1 to continue to learn about the profile. And this is why we expanded to 20 and then eventually 30 milligrams, so that we could see more about the slope of HPG mRNA induction, to see more about what's happening with target engagement, and continue to gather data on pharmacokinetics and safety and tolerability. So those data are helpful for us to inform the future development, and we're going to use those data to continue to build our plan for taking this into patients and expeditiously bringing this towards approval.
spk06: Perfect. Thanks for taking the questions. Look forward to it.
spk05: Thank you. Your next question comes from Piper Sandler. I mean from Ted Santoff of Piper Sandler. Your line is now open.
spk10: Thank you so much for taking the question, and congrats on a really exciting year. Again, appreciating that we're going to get an update at ASH on 6058. I wanted to get a sense for where things stand for us, map them out, and what potential next steps are. Thanks, guys. Hi, Ted. This is Chris again.
spk12: So, you know, as you know, you've heard us say continuously, we're very excited about the profile from us now from the data coming out of Redux 4, in which we show impacts on muscle structure, impacts on function, and patient-reported benefit. And we believe that this has potential to really importantly and profoundly impact patients with FSHD, and we're working expeditiously to bring this drug forward towards approval. Our base case continues to be that we'll have a Phase III trial. We're working really hard to prepare for that. We've looked deeply at the Redux IV data and natural history data and are developing a plan to start a Phase III trial that will ultimately answer those questions. We continue to be on track to meet with the regulators by the end of this year, and as soon as there's clarity about what that input is, we'll share that with you. We share the same goal as the community, which is to have a drug available that will profoundly and transformatively impact this course of disease. And I'm working with the regulators to do that goal.
spk03: And maybe, Ted, just to jump in on your first question regarding the data update. So we are, for 60 to 60 days, we remain in contract to be able to provide that update both to the higher dose cohorts as well as the elucidation of the mechanism by end of year. Based on timing of the abstracts as well as the timing of our trial, we are going to present that data outside of the ad quorum. That is, everything remains abstract to be able to do that. As we get closer to that, we'll be careful.
spk10: Thanks for that clarification. And just with this map, does it make sense to evaluate partnerships, even potentially overseas, if you keep U.S. rights? Thanks.
spk03: Yeah, I think, Ted, as Chris mentioned, based on the data that we generated, we're very excited to be interacting with the FDA and moving the program forward. So as we've talked about a lot in the past, when we went into the Phase 2b trial, we were really enthusiastic to be able to observe these patient benefits in what was a relatively small trial of only 80 subjects and a relatively short trial of only 48 weeks. So I think that gives us a lot of confidence and enthusiasm to move forward. I think as we then transition and look at this as a commercial opportunity, we're very much focused on the patient population and the unmet needs. So we know that these are patients that have this genetically defined rare disease. They are for the most part identified and it is a worldwide disease. So there's a patient population that I think is very much waiting for a therapy. And we're very fortunate that we are now building up our commercial leadership to put us in a position to be able to take advantage of that opportunity. So our focus is continue to bring it forward and try to get it to patients as quickly as we can.
spk10: Awesome, guys.
spk03: Thanks for the update. Thank you.
spk05: Your next question comes from Matthew Harrison of Morgan Stanley. Sir, your line is now open.
spk01: Good morning, everyone. This is Kostason for Matthew. Thanks for taking our questions, and Chris, good luck with next steps. Two questions from us on sickle cell disease. The first one is, can you talk a little bit about the relationship between the PK and the target engagement that you have seen so far with the available data, and whether the target engagement is C-max or AUC-driven? And secondly, We are wondering whether you are planning to share baseline mRNA levels at us. Thank you.
spk11: Hi, Costa. This is Chris. Yeah, thanks for the question.
spk12: So referring back to what we showed in August, you recall that we had achieved maximal target engagement at all three doses tested, so two, six, and 10 milligrams. It took a little longer for two to get there. By seven days, six and 10 were about the same at roughly the maximal level. And certainly by 14 days, all three dose levels were at maximal level. And if you recall, maximal inhibition defined by changes in histone trimethylation retained about 20 to 30% of PRC2 activity, which we think is an intrinsic competitive advantage of this particular mechanism. So there is something here regarding the concentrations the concentration relationship to target engagement, our preclinical data suggests that their relationship is based on exposure rather than C-max. The data that we showed back in August also implied that there is pretty long a residence time, that it takes about a week or so for the levels of histone trimethylation to return to normal, even though the half-life of the drug is only about nine hours. So again, it's
spk11: It's an exposure-driven relationship that has a durable effect. And then, Coach, maybe we could address the second question regarding mRNA levels.
spk12: Yeah, so that's not something that would be important in people that are healthy. It's more important in people that have sickle. And so this is not something that we intend to share. The most important information that we'll share about mRNA changes is the fold increase. baseline. When we start talking about the patient population in which there will be significant levels of HBG and ultimately of HBF where it will be relevant and where we'll have longer treatment durations, this is when we'll begin to report on these kinds of parameters.
spk03: And, Costas, I think we would also add one of the things that we've mentioned and been very enthusiastic about is just this consistency that we have observed to date, as Chris mentioned, across both mRNA as well as protein preclinically. So whether we looked at the Towns mouse model, the wild-type mouse, CD34 cells from sickle patients, from healthy volunteers, we have seen this very consistent two- to three-fold consistency induction of both mRNA and protein. And obviously, as we looked at our initial phase one healthy volunteer data, where we looked at mRNA, we were very enthusiastic to see this induction that was even beyond that two to three fold. So I think that gives us a lot of confidence as we look to translate into sickle cell patients. And the other element that does as well is just looking at some of these other opportunities, such as the gene editing and where we've seen this very meaningful translation from the CD34 positive assay preclinically into now what's being observed with BCL11A gene editing in patients. So I think all of that gives us confidence that as we get into patients here by the end of the year in the translation that we have the potential to observe.
spk01: Very helpful.
spk05: Thank you. Your next question. comes from Joseph Schwartz of SVV Lyrinc. Your line is now open.
spk07: Thanks very much. Congrats on all the progress as well. I was wondering how well developed is the understanding about potential natural variability around the thresholds of HPF that are associated with varying degrees of symptoms in sickle cell, and how will you be measuring symptoms in the Phase Ib study in STD patients? Is it just VOCs? Are there any other finer metrics you'll be evaluating?
spk03: Yeah, so Joe, why don't I turn it over to Paul Bruno, and he can speak to not only what is known from both data as well as other clinical trials about starting HBF levels, but also what is very clearly known about induction of HBF and the benefits from human genetics. And Joe, I think as we've talked about, inducing HBF is the only way to be able to treat the root cause of the disease. And we have such a wealth of data from these patients that have hereditary persistence of fetal hemoglobin that we're really able to build on that.
spk02: Just to expand off of what Brian said, so looking across the various clinical trials that are currently ongoing, so looking at CRISPR therapeutics and MARA and even past trials of hydroxyurea, as well as observational studies in sickle cell disease, population, we do feel very confident that the baseline level is in between 5 and 10%. As Brian alluded to, what we do know from the genetics in sickle cell disease individuals that also have mutations leading to hereditary persistence of fetal hemoglobin, we know that any increase in fetal hemoglobin levels results in amelioration of a broad swath of symptoms within sickle cell disease individuals. So thinking about things like anemia, BOCs, acute chest syndrome, as well as even bryolysis. And maybe I can have Chris Morabito speak to the phase 1B expectations there.
spk12: Yeah, great. Thanks, Paul. So, you know, as Paul mentioned, HPF is a surrogate. And increases in HPF in the setting of sickle cell disease are strongly associated with not only improvements in anemia, but also improvements in symptoms from anemia and improvements in things like VOC and VOC-related phenomena. We will be studying this in the 1B study for up to three months, which is about the time that we expect to have maximal impact on HPF in patients and see demonstrable significant changes in HPF. And we will, of course, be looking at symptoms. We don't expect in a three-month period in an open-label study without a placebo group, to be able to provide robust data on changes in VOC, certainly compared to anything, because we just have a baseline to compare to. But we will be looking for any signs that would impact that. Again, the surrogacy behind HPF in this setting, in particular when you have a drug that induces pancellular HPF, as our oral HPF inducer does, we do expect that taking this into a longer study, such as a phase two, we will be able to demonstrate significant improvements in clinical outcomes.
spk07: Okay, thank you. And then for your meetings with the FDA for losmapamod, I was curious how much patient advocates may be able to chime in on the merits and need for the drug. Can you give us any sense for how much bandwidth might be allocated by the FDA to receive the case for approval from the company versus patient advocates.
spk03: Yeah, Joe, why don't I turn it over to Chris to address that. And we can also just speak to some of the things that have been done from the community perspective in terms of engaging with the FDA, the patient-focused drug development days that took place in 2020, and just some of the discussions that have been having from a patient community that, as you point out, is obviously very enthusiastic about the potential for a therapy?
spk12: Yeah, so it's a wonderful question, and it's certainly something that we've been thinking deeply about, and we've engaged now. We've built now an internal group focusing specifically on patient engagement and patient advocacy. As Brian said, the patient advocacy network in the U.S. and outside the U.S., in Europe and in the U.K., for example, is very strong, very active, very engaged. And even outside of those organizations, the patients themselves are very engaged and very willing to help us and, importantly, to help regulators like the FDA understand the burden of this disease. Brian referred to a conference that was held in June of 2020, which produced a voice of the patient report. It was held in conjunction with the FDA. There were panels of experts, including patients, that participated in this conference. The number one report out of that was the patient request for a new therapy that would slow or halt disease progression, something like what we think the profile of Osmepamod can achieve. We're absolutely engaged with these organizations to communicate the burden of disease in FSHD and to help regulators understand what kinds of functional interventions or patient-reported interventions are important to this community, and we're engaged with this community as well to help us think about what kinds of assessments we need to be able to measure in ongoing clinical trials in order to provide the substantial evidence to support those approvals. FDA has been very engaged, and we are encouraged by this involvement and look forward to continuing partnership with the regulators.
spk07: Thanks again.
spk05: At this time, I would like to remind everyone, in order to ask questions, press start and the number 1 on your telephone keypad. Your next question comes from Judah Frommer of Credit Suisse. Your line is now open.
spk09: Hi. Thanks for taking the question, and congrats on all the progress. Just a couple follow-ups on the 1B design. Can you just remind us, you know, why you decided to dose with the 6-milligram dose and and not the 10, and how impactful could the 1B readout be to moving into Phase 2 versus the data generated in Healthy Volunteers, given that it is at one dose?
spk12: Yeah, so just to give you just the context of the study design, so it will be up to three months of therapy in patients with sickle cell disease and as all comers with sickle cell disease. And we're looking for, first and foremost, safety and tolerability, and then also looking for changes in key pharmacodynamic parameters, including HPF. And we think the three-month treatment duration gives us the opportunity to assess this. We anticipate having up to three dose cohorts, and we anticipate each cohort having up to 10 patients. We do have a DMC that will, it's an internal DMC that will be monitoring the study and giving us information at intervals that will inform continued development and progression through those cohorts. We decided to start at six because this is the dose level that achieved a three-fold induction in HBG mRNA in healthy volunteers. And as you've heard us say lots of times, our goalposts for this is a two- to three-fold induction on top of baseline in sickle cell patients. So we hypothesized that this is a dose that will have the potential for clinical benefits. We're also, you know, we believe that we will have at least the same amount of HBG induction in patients as we see in healthy volunteers. And there's also a potential for more HBG induction just because of the bone marrow environment, the retropoiesis environment in sickle cell compared to healthies. So, well, you know, we started at six in order to give us room in order to detect HBG changes, and ultimately HBF changes, HBF protein changes in patients. And we'll be looking at this continually as we dose through six. I'll just quickly finish this off. Subsequent doses will be informed by the incoming data and also by the PKPD model that we're building. Okay.
spk09: That makes a lot of sense. And then just can you remind us, from a clinical perspective, is you know, higher HPF better, or is there a kind of a threshold effect once you get to a 2, 3, 4x induction level?
spk12: Right. So, any increase from baseline has been demonstrated in genetic and clinical experiments to provide benefit. And, you know, we know from very good population studies that even the small change from baseline has potential impact overall survival, you know, over very long periods of time, but certainly has that kind of impact And we also know from the genetics that, you know, levels in the 20% range impact symptoms very well, and levels in the 25% to 35% range start to impact absolute symptomatology and can induce essentially a functional cure. What we're seeing from the incoming data from the gene editing programs is that very high levels of HPF, up to about 50%, can eliminate the disease and doesn't appear to cause any adverse events. So, you know, while we're seeing levels so far in healthy volunteers that imply we can induce to that kind of range, you know, obviously we'll see this in patients. We're not concerned about the potential for adverse events at this point related to that. Great. Thank you.
spk05: Thank you. This concludes the Q&A session for today. I would like to turn the call over to our CEO, Brian Stewart, for closing remarks.
spk03: Thank you. Thank you, everybody, for joining us today, and we appreciate your support of Fulcrum. Have a great day.
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