Fulcrum Therapeutics, Inc. (FULC) on Q2 2021 Results - Earnings Call Transcript
Operator: Good morning, and welcome to the Fulcrum Therapeutics Conference Call. Currently all participants are in 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. Christi Waarich, Director of Investor Relations and Corporate Communications for Fulcrum. Ma'am please proceed.
Christi Waarich: Thank you operator. 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 Bryan Stuart, President and Chief Executive Officer; Chris Moxham, Chief Scientific Officer and Chris Morabito, Chief Medical Officer. Let me quickly run through this morning's agenda. Given today's news, we're going to focus our call on the 6058 phase one healthy adult volunteer results. Bryan will begin a call with a corporate overview and key updates from the quarter. Chris Moxham will provide a review of the FTX-6058 deep preclinical data, Chris Morabito will review the clinical results and next programs and Bryan will open the calls for Q&A. With that, it's my pleasure to turn the call over to Bryan. Bryan.
Bryan Stuart: Thank you, Christi. Good morning, everyone. And thank you for joining us today. This past quarter was particularly notable for the significant progress in both of our clinical stage programs. In June, we announced positive results from the phase 2b ReDUX4 trial, where we were able to show the losmapimod slow disease progression, and improved function in patients with FSHD, but severe and progressive form of muscular dystrophy that currently has no approved treatments available. These results strongly support our belief that losmapimod has the potential to be a safe and effective therapy for FSHD patients. With these promising data from ReDUX4 in hand, we plan to meet with the FDA in the second half of 2021 to discuss potential next steps. Moving to FTX-6058 today, we are very pleased to report compelling results from our ongoing phase one trial and healthy adult volunteers. As many of you know, the current treatment landscape for sickle cell disease includes therapies that target only select symptoms. The introduction of an oral therapy that can successfully target the root cause of sickle cell disease would represent a major advancement. We are especially excited about the results from this trial, both in terms of tolerability as well as the impact we see in the induction of fetal hemoglobin mRNA and increase in efforts ocular sites. In this trial, we saw an impressive 4.5 fold induction of fetal hemoglobin mRNA. We also saw a 4.2 fold increase in particular size, which indicates fetal hemoglobin production. And we achieve maximal carbon engagement. Building on our extensive preclinical research these results provide proof of biology and mechanism. We're also pleased to share that FTX-6058 has been generally well tolerated to-date and the pharmacokinetics support once daily oral administration. Encouragingly these results provide the first evidence that FTX-6058 may be able to achieve or exceed the two to three fold HbF induction we observed pre-clinically. This two to three fold HbF induction threshold would not only be superior to hydroxyurea the current standard of care, but is also predicted to provide meaningful clinical benefit to sickle cell patients. With these results in hand, we remain on track to initiate a phase 1B in sickle cell patients by the end of the year and plan to initiate a clinical trial in non sickle cell hemoglobinopathies in 2022. I will note that both of our development programs came from our Fulcrum Seek discovery platform, which is a powerful and differentiated approach to drug target identification and the innovation backbone of our company that has allowed us to rapidly identify novel high quality targets then modulate the root cause of genetically defined rare diseases. By enabling drug discovery at unprecedented scale in disease relevant settings, Fulcrum Seek creates an unparalleled opportunity to efficiently grow our pipeline. We expect the work we are doing at Fulcrum Seek will enable us to submit to new INDs by the first quarter of 2023. In addition, Fulcrum Seek has also enabled our ongoing collaborations with both Acceleron and myocardium, which continues to proceed well. As you can see, we continue to make important progress across our clinical development programs, research collaboration and discovery platform and with a cash runway that takes us into the first quarter of 2023 we expect to have meaningful updates from multiple key initiatives in the near term. With that, I'll turn the call over to Chris Moxham to speak more about our preclinical work with FTX-6058.
Chris Moxham: Thanks, Bryan. Sickle cell disease is a genetic disorder of the red blood cells caused by mutation in the HPV gene. It is the most common type of inherited hemoglobin apathy, and affects an estimated 100,000 people in the United States and millions more worldwide. In healthy individuals red blood cells are round and biconcave, enabling efficient circulation through small blood vessels to carry oxygen to all parts of the body. In an individual with sickle cell disease, the red blood cells take on a characteristic sickle shape. Sickle cells often die prematurely. Also known as hemolysis, which causes a constant shortage of red blood cells or anemia. Also, when sickle red blood cells travel through blood vessels, they often get stuck and restrict normal blood flow. When this happens, sickle cell disease individuals can experience what is known as a vaso-occlusive crisis or VOC. Beyond anemia and VOCs people living with sickle cell disease typically suffer from other serious morbidities such as stroke and acute chest syndrome. Together these complications significantly impact lifespan. Current therapies are unable to address broad sickle cell disease symptomology and thus underscores the tremendous unmet need the remains in this diverse population. The therapeutic rationale or Fulcrum is to induce fetal hemoglobin or HbF. Human Genetics clearly show this mechanism can treat the root cause of disease. People who carry the sickle cell mutation, as well as additional mutations that promote hereditary persistence of fetal hemoglobin, present with HbF levels that are often elevated above 20% and that are associated with asymptomatic disease. These observations suggest that novel therapies that can achieve similar levels have the potential to provide a functional cure. But I'd also like to point out is that individuals with sickle cell disease have baseline HbF levels that are typically between 5% and 10% of total hemoglobin. This implies that an effective HbF inducer may provide meaningful clinical benefit by increasing HbF levels two to three fold above baseline. It has been shown both clinically and genetically that such levels of HbF can have a transformative impact for patients along the spectrum shown on the blue arrow, including progressively reduced mortality, reducing recurring pain crisis events and increased likelihood of asymptomatic presentation. Using our Fulcrum Seek drug discovery platform we identified EED, as a biological target capable of robust HbF induction. EED is a non catalytic subunit of the PRC2 complex. PRC2 propagates histone trimethylation an epigenetic mark that is associated with decreasing HbG mRNA and HbF protein expression. We developed FTX-6058 as a highly potent oral small molecule EED inhibitor, capable of decreasing histone trimethylation levels through PRC2 inhibition and thereby inducing HbG mRNA and HbF protein expression in red blood cells. FTX-6058 has outstanding drug like properties and in addition to potent EED binding and inhibition of PRC2 this plays a highly selective and clean off target profile. We were also issued a composition of matter patent which provides protection until 2014. We have profiled 6058 across numerous in vitro and in vivo preclinical models. In both healthy and sickle cell disease models, we observe a consistent two to three fold induction of HbF protein and we observed strong correlations between mRNA and protein expression. As seen on the right, we are showing mRNA and HbF protein changes from healthy CD-34 positive cells and the Townes mouse model that highlight this consistent two to three fold correlation of mRNA and protein. The connectivity of concentration dependent increases in target engagement with induction of HbG mRNA and HbF protein expression is a very consistent finding that we observed throughout the preclinical data set we generated to-date. In preclinical studies the inhibition of EED with FTX-6058 also results in similar levels of HbF induction as compared to those reported with gene editing. Specifically in erythroid cells derived from two CD34 positive cells, FTX- 6058 achieves a maximum of three fold HbF induction in healthy and sickle cell donors. This is similar to publish data from vertex and CRISPR therapeutics, demonstrating an approximate three fold HbF induction in CD34 positive cells from healthy donors by CTX-001, a BCL-11A gene editing approach now being studied in a phase 1, 2 clinical trial. On the left side of this slide, you can see we've profiled CD34 positive cells that were obtained from healthy and sickle cell donors or a donor who had the sickle cell trait. In all cases, we have a robust increase in the amount of HbF and response to treatment with FTX-6058. But we observe as the characteristic two to three fold increase above baseline that equates to absolute HbF increases between 8% and 25%. If these post treatment values were to translate into the clinic FTX-6058 has the potential to provide meaningful benefit and even potentially curative levels of HbF administered as a once daily oral pill. As we think about the value proposition of an oral small molecule that can induce HPF levels two to three fold we believe this could be the preferred treatment option for patients, providers and payers. As I mentioned, baseline HbF levels in sickle cell disease patients are typically 5% to 10%. Based on a strong body of literature generated today, inducing HbF can address the root cause of sickle cell disease. In contrast with symptomatic treatments or stem cell transplant regimens used in conjunction with gene editing and effective oral small molecule HbF inducer such as FTX-6058 has the potential to be disease modifying, addressing sickle cell disease pathology and symptomatology. Coupled this potential for broad therapeutic benefit with the convenience of oral administration and distribution at scale to meet them medical need of a global patient population, we believe that FTX-6058 may truly transform the treatment landscape. You'll see that in our phase one healthy volunteer trial, we've included exploratory measures of HbG mRNA in that particular sites. One of the key reasons we're quantifying these students of the biology of erythropoiesis in healthy individuals. The process of erythropoiesis greatly influences total mRNA and total protein levels as human stem cells in the bone marrow, differentiate and eventually enter circulation as mature red blood cells. Moreover, the proposed side of action for FTX-6058 is on the human stem cells that reside in the bone marrow. As you can see, these newly exposed cells will take approximately two weeks to differentiate into particular sites and enter the circulation from which we are sampling. This provides a narrow window of time to measure any HbG mRNA changes that may be occurring in the context of a 14 day study. Thus, we develop the highly sensitive and robust droplet digital PCR assay to quantify HbG mRNA. Also, as particular sites represent the first opportunity to determine if any HbG mRNA increases have begun to translate to HbF protein in the context of a 14 day trial. We utilize particular site measure that relies on specific immuno detection of HbF to quantify any early change in HbF protein. Before turning the call over to Chris Morabito, I'd like to thank the team at Fulcrum, who's working so hard in this program, and the volunteers who participated in this trial. It's a fantastic example of innovative drug discovery that has the potential to make a real impact on people living with sickle cell disease. Chris?
Chris Morabito: Thanks, Chris. I'd like to take a moment to remind everyone that the results we will be sharing are from our ongoing phase one clinical trial and healthy volunteers. As a reminder, the aim of the ongoing phase 1 is to evaluate safety, tolerability and pharmacokinetics of FTX-6058 treatment. The trial is also collecting pharmacodynamic data to assess target engagement HbG mRNA levels and increases in particular sites, which are particular sites that contain HbF protein. Here you can see the design of the trial and the doses being studied in the SAD and MAD cohorts. We've also included the expected target engagement and pharmacodynamic effects thresholds derived from PK/PD modeling of preclinical data. Based on this modeling, we expected that the target engagement and pharmacodynamic effects would be observed in a 6, 10 and 20 milligram MAD cohorts. To date, we have completed SAP cohorts 1 through 6 and MAD cohorts, 1 through 3. FTX-6058 was generally well tolerated in all the SAD and MAD cohorts completed stage. There were no serious adverse events and no discontinuations. All treatment emergent adverse events deemed at least possibly related to 6058 were mild in both the SAD and MAD cohorts. There was one grade 4 in the 10 milligram cohort that was determined to be unrelated to study drug. These tolerability and safety data are consistent with expectations and support advancing this trial. FTX-6058 TK profiles demonstrated those proportionality across the SAD and MAD cohorts that mean half life is approximately six to seven hours, which was longer than what we had originally modeled. This resulted in greater exposures at lower doses which we believe directly influence the target engagement and pharmacodynamic effect observed at lower doses. Next, we will share the results from the three exploratory endpoints measured in our phase one trial. Shown on this slide as a target engagement data demonstrating potent and robust inhibition of histone trimethylation. The key epigenetic mark facilitated directly by PRC2. We collected samples of baselines denoted as T-1. We then collected samples of measured target engagement at these 7 and 14 on treatment. And at the safety follow up visit denoted SFU which occurred 7 to 10 days after the last dose at day 14. These results demonstrate that maximal target engagement was achieved by day 7 in the 6 and 10 milligram cohorts. Maximal target engagement was also achieved at 200 grams after 14 consecutive days of treatment. All note that subjects retained about 20% of baseline histone trimethylation levels at maximal target engagement consistent with the preclinical data we've generated. Overall, these clinical results demonstrate that FTX-6058 is a potent inhibitor of PRC2 activity. Next, we will share the HbG mRNA clinical data. FTX-6058 treatment resulted in both time and dose dependent increases and HbG mRNA demonstrating proof of biology. Here we're presenting these pharmacodynamic effects in data S3 panels, the 2 milligram, 6 milligram and 10 milligram dose MAD cohorts plotted as fold induction over placebo at each time point. There is clear evidence of those proportionality. At 2 milligrams there is evidence of HbG mRNA induction that these 7 and 14 are not statistically significant. In both the 6 and 10 milligram cohorts, we observed statistically significant HbG mRNA induction, but the 10 milligram of cohort achieving a mean 4.5 fold induction after 14 days. You can also see we're getting up to a maximum of 8 fold induction in the 10 milligram cohort as indicated by the 95% confidence interval range. Encouragingly, all of the results presented in the 6 and 10 milligram cohort demonstrates statistically significant changes from baseline. I'll also point out that the HbG mRNA induction response is highly durable. You notice that a CT follow up 7 to 10 days after the treatment period, subjects maintained the HbG mRNA induction observed at day 14, which we believe will translate to HbF protein expression as well. This type of durability is also consistent with what we've demonstrated pre-clinically and the Townes mouse model. Before we move on, I want to contextualize this mean 4.5 fold HbG mRNA induction. I will remind you that we observed a two to three fold induction of mRNA across multiple models pre-clinically, suggesting that these results are meeting and potentially exceeding the induction thresholds predicted to provide meaningful clinical benefit for sickle cell patients. I'll also note that pre-clinically HbG mRNA induction was also strongly correlated with each HbF protein induction. Last, we will present the F-reticulocyte clinical results where we against the evidence of a dose proportional PD effect. To remind you an F-reticulocyte is a reticular site that contains HbF protein. While we did not observe F-reticulocyte increases have been 2 milligram cohort after 14 days on treatment. We observed statistically significant increases at safety follow up after the 14 day treatment periods and both the 6 and 10 milligram cohorts. FTX-6058 treatment and the 10 milligram cohort demonstrated a mean 4.2 fold increase in particular sites which indicates that persistent HbG mRNA induction is translating the HbF protein and strongly correlates with the HbG mRNA induction observed to-date. As we laid out earlier, the kinetics observed across these target engagement and PD endpoints are consistent with the and healthy individuals. We observed maximal target engagement by 7 days, HbG mRNA induction by day 14 and F-reticulocyte demonstrating HbF protein expression by 21 to 24 days. These results demonstrate a robust relationship between target engagement, mRNA induction and protein expression and the healthy volunteers setting. In summary, the results presented today meet the induction thresholds predicted to provide meaningful clinical benefits of sickle cell disease patients. Extensive genetic and clinical literature indicate that a two to three fold induction in HbF protein as a potential to translate to broad clinical benefits. We have also demonstrated pre-clinically that HbG mRNA induction and HbF protein expression are highly correlated. These clinical results demonstrate proof of biology and mechanism. Additionally, we predict the mean 4.5 fold induction in HbG mRNA demonstrated to date is predicted to translate the HbF protein based on the strong correlation between mRNA and protein expression based of certain pre-clinically as well as the strong correlation observed between HbG mRNA and F-reticulocyte clinically. If these HbG mRNA induction results continue to translate in the clinic, we believe FTX-6058 could provide clinical benefits to sickle cell patients. In terms of next steps for the program, we anticipate sharing additional results from the ongoing phase one trial at a medical conference at the end of the year, pending abstract acceptance. Based on what we reported today. We also intend to involve sickle cell patients in a clinical trial in the fourth quarter of this year. The multiple dose phase 1B trial would start with the 6 milligram dose and include a treatment period of up to three months. It will be designed to confirm and build on our current results with an aim to demonstrate early proof of concept in individuals with sickle cell disease. We are planning that the subsequent study will be a phase 2/3 clinical trial that will start in 2023. In addition, the clinical results to-date support the initiation of a clinical trial and non sickle cell disease hemoglobinopathies, including beta thalassemia and we intend to submit an IND by the end of this year. With that, I'll turn it back to you, Bryan.
Bryan Stuart: Thanks, Chris. The clinical results presented today exceeded our expectations and expand on our understanding of the preclinical data that we've generated. These results provide proof of biology and mechanism and the increases in F-reticulocyte also provides the first indication that robust increases in HbG mRNA are translating to HbF protein, the opportunity to bring a new oral once daily therapy to people living with sickle cell disease is a very exciting prospect. And we believe FTX-6058 has the potential to be a significant advancement in treatment in the years ahead. These results further bolster our plans to enroll sickle cell patients in a clinical trial by the end of the year. 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 compelling data to-date. And we look forward to identifying additional programs with great potential from our product engine. As we seek to expand our development pipeline. We look forward to keeping you updated on our progress in the months ahead. Operator, you may now open the line for questions.
Operator: Thank you, sir. your first question is from the line of Ted Tenthoff from Piper Sandler. Your line is now open.
Ted Tenthoff: Great, thank you very much. Remarkable results. Is there any from a modeling what do you anticipate to see from 20 migs and just thinking about the differences between the healthy and sickle cell patients? Again, appreciating that we haven't seen protein yet. But is there any reason to think that this might work either better or worse in patients? Thank you so much. And congrats. It's great data.
Bryan Stuart: Yes, Thanks Ted. I turn it over to Chris Morabito and we can speak a little more to the phase 1B study and what we would anticipate seeing there.
Chris Morabito: So Ted thanks for the question. The first question was about 20 milligrams. I assume you mean the ongoing clinical trials. Is that correct?
Ted Tenthoff: Yes.
Chris Morabito: Thank you. So first, I think that we just go by the PD biomarkers. I think we will not exceed the target engagement that we've achieved. We've already achieved maximal target engagement at all three doses. I don't think we'll exceed that. There might be some differences in the kinetics to get to maximum target engagement, but the limit will be exceeded. HbG mRNA induction could be increased. And again, we will likely see a difference in the kinetics to get to a maximal amount. We expect there will be an increase, but I can't predict what that number will be at this point. And as similarly with F-reticulocyte, we would expect that we would see an increase over what we currently have today especially in terms of kinetics. So the time course of when that will happen. We are, regardless thrilled about what we're seeing so far in the 6 to 10 milligram seeing over two to three fold induction, which is what we predicted to us as a very meaningful result. And we look forward to continuing that, continue with that goalpost in mind as we move forward into the phase 1B study. Your second question was about what we might expect to see in sickle cell patients versus healthy volunteers. We know from our preclinical data that we would expect to see at least the same amount of increases just based on what we have seen in our preclinical models which demonstrate equally robust increases in health ease compared to sickle cell patients. Having said that, in patients, human patients where the bone marrow is a bit more permissive, and where RBC half-life is shorter because of the pathology of this disease, it's quite likely that we will see more significant changes, more fold induction or potentially faster induction compared to what we're seeing in health ease. Of course, this is the point of the 1B study that will be starting later on this year and we'll certainly be excited to share those results as they come forward.
Ted Tenthoff: Great, excellent. Thank you guys. Congrats.
Operator: Your next question is from the line of Dae Gon Ha from Stiefel. Your line is now open.
Dae Gon Ha: Thanks for taking our questions, and congrats for me as well. But just to kind of follow up on the next plan or the patient trial phase 1B MAD study. But just wondering, given the chronic dosing that's likely from this oral administer drug, what are your thoughts on I guess the treatment magnitude that you can expect and you mentioned two to three fold. So should we expect 4 to 4.5 that we saw on the healthy volunteers or can you provide a little bit more, I guess, bookends around that? And then second part to that question is, I guess, given the chronic dosing, what kind of safety signals should we be expecting going forward, given that this is basically tampering with the epigenetics? Thank you.
Bryan Stuart: Thanks, Dae Gon. I turn it over to Chris Morabito again, and you can break that question up into two answers. One is just realizing increases that we're observing relative to the starting fetal hemoglobin levels that most sickle cell patients have. And then we can comment on what we've observed from a safety tolerability perspective.
Chris Morabito : Great, so thanks. So phase 1B will be our first chance to see the effects of this drug in patients. We're really excited to doing that. And as indicated, that will be an open label study. So we'll be able to get a feedback relatively new, as progress to the study. The goalposts for the study will be a sort of threefold induction. But as ultimately, as Bryan intimated, setting up this answer, what we want to do is get to a percent, a target percent in patients somewhere between 10% and 30%, which is where we know based on genetics, and other clinical data, we can see potentially profound effects on patients. Patients with sickle cell disease, start with roughly 5 to 10% HbF level and increasing by a magnitude of two to three would get, like 10% to 30% rate, which is where we would expect to see important clinical changes. You could potentially start to see even in the phase 1B, but certainly which we would expect to observe in the future Q3 study. In terms of the safety and tolerability so far, we're actually really quite pleased with what we're seeing. This has a very well tolerated while based on phase 1 results, the date is two weeks of ducting, as you point out this is not chronic dosing, but based on the results and based on the levels that were achieved from a pharmacokinetic perspective we're optimistic that moving into patients over a longer period of time, they'll give us these kinds of results as we're seeing now and healthy.
Dae Gon Ha: If I can just add one more question. This may be a really dumb question. But these are healthy volunteers, 4.5 fold increase. Any chance you could put some percentage value?
Bryan Stuart: Dae, I am sorry we have having a tough time hearing you.
Operator: Yes, ma'am. I'm sorry. Sir, you might have been speaking on your speakerphone. Please pick up your handset so we can hear you clearly.
Dae Gon Ha: Can you guys hear me now?
Bryan Stuart: We can. Thanks.
Dae Gon Ha: So just a quick follow up was, this might be a really dumb question. But you just mentioned the percent target being 10% to 30% in the patient study. But any chance we can do something similar exercise in these healthy volunteers. Now that you've seen the four fold increase or induction? Do we even get the percentage value on the HbF? Or is that completely out of the question? Thank you.
Bryan Stuart: So yes, Dae Gon, I would like to I turn it over to Chris Moxham? We can speak more to what we've seen pre-clinically as CD34 is both from sickle donors as well as healthy donors.
Chris Moxham: Sure, so again, what we've observed pre-clinically is this two to three fold induction above baseline. And in absolute terms, we have certainly seen absolute levels of HbF, as I pointed out with upper end of 25%, absolute increases of 25% above baseline. So we've definitely been able to achieve levels that are associated with a curative effect. In the context of the healthy volunteer study again, this is only a frankly a 21 day study. 14 days of dosing within the safety follow up period and as we highlighted, we need to then overlay the normal process of erythropoiesis, which has been pointed towards detecting HbF protein in the context of particular sites. The question of whether we can quantify absolute levels of HbF in the context of a 21 day study is really not possible. And that would require a study of longer duration. And which will be the focus of a measurement that using HPLC to quantify HbF in absolute terms as a typically done in a longer duration, phase 1B study.
Dae Gon Ha: Awesome. Well, thank you very much for those responses. I'll hop back in the queue.
Operator: Next question is from the line of Joseph Schwartz from SVB Leerink. Your line is now open.
Joseph Schwartz: Thank you very much and congratulations from me as well. I was wondering if you have any more thoughts on why you saw a saw greater efficacy in healthy volunteers than the two to three fold increases in mRNA you expected based on your preclinical work? Do you think that's purely due to greater exposure due to longer half-life than expected? Are there any other factors in your view that might have contributed?
Bryan Stuart: Sure, that's a very good question. And we don't have any clear indicators as to why today. I think, a notable difference perhaps between the preclinical data again, where we showed very robust two to three fold increases in HVF. In, for example, in the town's mouse model system, which again is humanized in the context of the globin genes, but still is operating under the control of the mouse or the murine transcription factors. Now, we're going to feel fully humanized system in the healthy volunteer and that may in fact be accounting for some of the differences we're seeing in the level of fold induction that have exceeded the levels that we saw in the preclinical study. We are certainly very pleased with these results. Again, we remain focused on a two to three fold induction to provide meaningful clinical benefit and certainly looked to see whether this translates now into the sickle cell setting. And as Chris Morabito implied and commented that we believe that the sickle cell setting likely will be even more permissive, given the fact that we know that erythropoiesis is elevated baseline HbF levels are elevated, and that the red blood cells have any shorter half life in sickle cell setting. So think that whole context gives us a greater opportunity to see even a greater induction.
Joseph Schwartz: That's very interesting. And then, I recall that FTX-6058 has been developed to have high pan-cellularity. I was wondering if you could talk about whether you have been able to evaluate that attribute and healthy volunteers and what the implications are for when you get into patients?
Bryan Stuart: Yes, And I'll turn it over to Chris. And we can remind you of just what we did observe pre-clinically. And then what we expect here.
Chris Morabito: Yes. So again, pre-clinically, what we did observe is a very robust pan cellular induction where now 90% of the cells were demonstrated to be expressing very high levels of HbF protein. In the context of the healthy volunteer study, we're not able to assess that. And it's really would be in the context of the sickle cell study where we'd have a much greater chance to comment and collect data that would speak to the pan cellular induction, but certainly, again, based upon the preclinical data either in healthy volunteer cells that were derived from a healthy donor or CD34 cells obtained from a sickle cell donor, we see a very consistent two to three fold induction and a very consistent pan cellular induction in either setting.
Joseph Schwartz: And then, if I could just ask the bigger picture question. What do you think are the implications of this work on the broader Fulcrum Seek platform? Are there other particular programs in your development pipeline, where there might be more direct read through than others based on any similarities in the biology and/or your approach to modulate gene expression in a congruent way?
Bryan Stuart: Thanks, Joe. Broadly, obviously, we're very enthusiastic, both about this data, and the FSHD data in terms of being validating for Fulcrum Seek and our approach. So both of these programs, as we talked about, came out of the Fulcrum Seek engine, one of them 6058, we use our own medicinal chemistry and created this compound that we're very excited about in the and the other FSHD we identified a target that had chemical matter that we were able to see in license. So we feel like this is great validation. We're very excited with 6058 to be taking that into other select hemoglobinopathies as we referenced and feel like that really brought in the opportunity. And additionally, I would say hematology as we think about Fulcrum Seek remains an area of focus, and the type of commitment and expertise we're building in the area. We feel like we're really lend itself to other programs as well.
Joseph Schwartz: Great. Well, congrats. Thank you.
Operator: Your next question is from the line of Matthew Harrison from Morgan Stanley. Your line is now open.
Matthew Harrison: Good morning, I guess a couple things I want to touch on. So I know others have asked about higher doses and dose range. It just wasn't clear to me. So maybe if you could just expand. Is your expectation to look at a wider dose range, or do you feel happy with 10 migs and that's what you're going to take into the next study? And then secondly, I guess I want to ask a question about sort of cumulative change or aggregate change. So would you expect in sickle cell patients being dosed over a longer period of time for these improvements to get larger than what you've seen in sort of the short period of time and healthy volunteers? Thanks.
Bryan Stuart: Thanks Matthew, and turn over to Chris, and we could talk about how we're thinking about dosing in the 1B as well as the second question to move to change.
Chris Morabito: So as I said, the first dose for the upcoming phase 1Bv study will be six milligrams, and we intend to dose up to three months. In open label way. At six milligrams, we haven't yet determined the second dose for the study. It could be 10 milligrams based on the data that we reviewed today, it may be 20 milligrams based on the data that will come in from the LT volunteer study that's still running. We want to choose two doses that will give us those ranging information in the 1b study, so that we could select one dose for the potentially pivotal phase two study. So the broad range of doses in the 1b would give us a broad range of PK and PD responses with which we can build a robust model and select that dose, can't yet comment on what the upper end dose will be. But that's the approach that we'll take as we move that study forward. And we'll make the dose determination as we get closer to the initiation of the trial. Now, in terms of the magnitude of changes, again, we stick to what we've been saying that our goalposts here would be a two to three fold increase in sickle cell patients at any either of the doses or any of the doses that we test and the phase 1b study, we of course, would be thrilled to see increases over that, especially in HbF protein levels. But as I mentioned before, and Chris and Brian have reiterated that two to three fold increase would be transformational, particularly when this is given us an oral medicine.
Operator: Your next question is from the line of Tazeen Ahmad from Bank of America. Your line is now open.
Tazeen Ahmad: Okay, good morning. I think that's me. Hi, guys. Just wanted to ask a couple of questions for points of clarification. So just so that I'm clear, when should we expect to see a report the results of increases in HbF protein, and then have a couple of follow up?
Bryan Stuart: So we plan to begin enrollment of the Phase 1b trial in the fourth quarter of this year. And we plan on providing an update in the second quarter of next year.
Tazeen Ahmad: And then, how long from the time you start treating patients would you ideally expect to start to see the impact on HbF? Is this something that would be immediate or would it take a certain level of time, a certain amount of time? And then can you just remind us what you're expecting your dosing regimen today?
Bryan Stuart: Yes. So as we discussed, as we laid out in the slide, where we talked about the process the first time that you would expect to see HbF protein, quantifiable HbF protein would be in patients around a month, and then after three months, we would be much more likely to see that. It just takes longer for the HbF to be quantifiable in the periphery.
Tazeen Ahmad: And our patients, the patients uniformly respond, or is there variability.
Bryan Stuart: So, go in Chris.
Chris Morabito: Yes, to that question, what we've seen pre-clinically is that all the donors that we have tested to-date have a very robust increase to FTX-6058, whether they're derived from a healthy donor, or sickle cell donor, or even that donor with sickle cell trait that is in contradistinction to hydroxyurea, which has a much more varied response, and frankly, much weaker efficacy in the context of our preclinical data. So we're very encouraged by the fact that we see universally today a very robust and significant increase in HbF protein levels after treatment 6058.
Tazeen Ahmad: And then last question for me based on that would you expect that the entire SAD population would be eligible or would you have certain criteria at least for trial enrollment?
Bryan Stuart: Yes. The entire population is eligible for this. Absolutely.
Operator: Your last question is from the line of Judah Frommer from Credit Suisse. Your line is now open.
Judah Frommer: Thanks for the question. Just one on the potential regulatory path forward, I think in the past, you've referenced a competitor's bar of 3% improvement in HbF protein, I mean, the results today seem to indicate that you should be or could be well above that. So any thoughts on that bar, any conversations with the agency that may help you move forward on either a biomarker or another perspective?
Bryan Stuart: Yes. I would say in terms of the bar is, as you referenced, there is just a very clear understanding from human genetics, from these patients who have hereditary persistence of fetal hemoglobin, that even these small increases and referenced as a percentage of fetal hemoglobin can have very meaningful impacts on patients. And obviously, the greater increases in fetal hemoglobin have an even greater impact on patients up to the point where they're essentially asymptomatic. What we've observed and relative to that 3%, which would be maybe about a little over a one fold increase, what we're observing is significantly greater. So we're very enthusiastic about that. Our goal right now, as Chris Morabito mentioned is to get into a phase 1B trial, be able to select a dose with the hope to then move into a phase 2/3 registration trial and the opportunity to potentially bring this to patients as quickly as possible.
Judah Frommer: Great, thanks.
Operator: There are no further questions. And with that, this concludes today's conference call. Everyone thank you for attending. You may now disconnect. Have a great day.
Christi Waarich: Goodbye.
