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

Good morning, and welcome to TX-6058 Phase I healthy volunteer trial update. [Operator Instructions] I would now like to turn the call over to Christi Waarich, Director of Investor Relations and Corporate Communications at Fulcrum. Please proceed.

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 time lines 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; Dr. Gerd Blobel from the Children's Hospital of Philadelphia; Judith Dunn, President of R&D; and Chris Morabito, Chief Medical Officer; Paul Bruno, our Senior Director of Corporate Development will also be available for Q&A. Let me quickly run through this morning's agenda. Bryan will begin the call. Dr. Blobel will provide an overview of fetal hemoglobin induction as a therapeutic strategy in sickle cell disease. Judy will review the preclinical data supporting FTX-6058 and share new insights on its mechanism. Chris Morabito will provide an update on the 20- and 30-milligram cohort in the healthy volunteer trial, and Bryan will open the call for Q&A. With that, it's my pleasure to turn the call over to Bryan.

Thanks, Christi. It's been a great year for Fulcrum. In June, we announced exciting data for losmapimod, which we believe has the potential to slow or stop progression of FSHD. FSHD is a relentless and debilitating form of muscular dystrophy. The data we reported showed patient benefit and even improvement across a number of measures of muscle health, function and patient-reported outcomes. And we look forward to providing an update on the program in the first quarter of next year. In August, we reported promising initial results with FTX-6058, our oral HbF inducer from our Phase I trial in healthy adult volunteers. As you'll hear from Chris Morabito later on, the data we are reporting today from the higher dose cohorts affirm our conviction in FTX-6058 as a potentially transformative oral therapy for sickle cell disease and other hemoglobinopathies. We are on track to initiate the Phase Ib in people with sickle cell disease and to submit an IND in other hemoglobinopathies by year-end. We are joined today by Dr. Gerd Blobel, who will share his insights on fetal hemoglobin induction as a therapeutic strategy in hemoglobinopathies. Dr. Blobel is at Children's Hospital of Philadelphia, where he runs the lab and studies molecular biology of global gene expression. He's also the Co-Director of the UPenn Epigenetics Institute. We are pleased to have him with us today. With that, I'll turn it over to Dr. Blobel. Gerd?

Thanks very much, and good morning to all. I'm very pleased to be included in this presentation. First slide. So sickle cell disease and the thalassemias are devastating multisystem disorders that are caused by genetic alterations at the globin gene cluster. The painting on the left was made by a sickle cell patient shortly after pain crisis. He passed away very recently from complications of the disease. On the right are 2 patients with thalassemia intermedia. The pictures, I think, speak for themselves. Next slide. By means of a brief introduction, red blood cells carry hemoglobin. Each hemoglobin complex is made up of 2 alpha type and 2 beta type globin chains. Importantly, the type of globin chains produced in red blood cells changes throughout development. Next slide, please. As illustrated in this cartoon, the beta type globin genes fall into 3 categories. Embryonic, fetal and adult. The fetal type globin genes are expressed in the liver during the second and third trimester of gestation and are silent after birth. At that time, red blood cell formation shifts to the bone marrow and adult type globin genes take over. This explains why diseases caused by genetic alterations in the adult type globin genes manifest after birth. Next slide, please. So the interest in the molecular mechanisms underlying the switch from fetal to adult globin production was fueled by the desire to reverse the switch because it has been known for some time that elevated HbF levels and fetal globin levels, I should say, counteract sickle cell formation. There's very strong genetic evidence to support that fact. For example, there's a benign genetic condition called HPFH or hereditary persistence of fetal hemoglobin in which the fetal genes stay on to varying extent in adult life. Core inheritance of an HPFH causing mutation, together with a sickle mutation, it generates the symptoms of the disease. Next slide. This is an older clinical study demonstrating that elevated fetal hemoglobin levels are associated with a longer lifespan. Now it's really important to note that while ideally one wants to achieve fetal hemoglobin levels of 30% or greater to essentially eliminate all symptoms of the disease, the clinical impact of elevated fetal globin levels is a continuum. And even less than 30% total fetal hemoglobin levels can be of considerable clinical benefit with reduced suffering, fewer pain crises, fewer hospital visits and so on. Next slide. I'm sure that most of you have seen the advances in gene therapy, which comprise diverse strategies ranging from expression of a fetal globin transgene as shown in the web panel on the left. Genome editing as in the case of recent trials -- a recent trial that targets a regulatory element of a gene called BCL11A, which is a fetal globin gene repressor, or in the yellow panel on the right, depleting BCL11A by expressing in red blood cell precursors, a hairpin RNA that targets BCL11A. Now please note that all of these approaches acquire autologous bone marrow transplants with associated risks. Plus, in spite of very promising results, these approaches are still largely experimental, require highly sophisticated medical centers and are hugely expensive. Next slide. This really illustrates the need for pharmacologic intervention and the development of small molecules and drugs to reverse the switch. Next slide. While the problem of hemoglobin switching has been studied for several decades, a breakthrough came from GWAS studies, in which natural variations in fetal globin levels could be linked to at least 3 gene loci. These unsurprisingly include the globin gene cluster itself, but also the BCL11A and mid genes, BC11A I just mentioned a second ago. Next slide, please. BCL11A and LRF, another transcription factor, which was not identified by GWAS, are 2 DNA binding proteins that recruit transcriptional cofactors to silence the fetal type globin genes. However, DNA binding transcription factors are notoriously hard to drug. In spite of several years of efforts, no small molecule has been found that directly interferes with BCL11A activity. This has prompted the search for new regulators that might modulate BC11A activity or its expression levels. And as you will see, FTX-6058 down regulates BC11A levels. I should point out that LRF is a potent fetal globin repressor also, but interference with LRF leads to undesirable effects on cellular maturation, making it a much less attractive target. So what are other regulatory mechanisms? And what are other ways to control BCL11A activity or levels? Next slide, please. I hope this is the slide now on hemoglobin switching and co-repressors. So several labs, including ours, have pursued the identification of regulatory molecules, either by testing candidate proteins such as those physically bound to BCL11A or via candidate testing or unbiased screening approaches. The examples shown on this slide include 2 proteins demarcated by arrows that are part of the so-called polycomb repressor complex. Interference with expression of these molecules augments fetal globin production, which is annotated on the Y-axis. Next slide. I should add that my lab has carried out extensive CRISPR-based screening for novel fetal globin regulators, and we also came across polycomb proteins, which means that at least 3 independent labs and probably more have come to similar conclusions as to a role for polycomb proteins in the regulation of fetal globin levels. Next slide. What Fulcrum has found, and you'll hear a lot more about this in the next presentation, is a genetic or pharmacologic interference with a PRC2 component called EED, down regulates BCL11A and MYB expression, accounting at least in part for the gains in fetal globin production. So with that, I'll hand it over to the next speaker, and thank you very much.

Thank you, Gerd. Sickle cell disease affects an estimated 100,000 people in the United States and millions more worldwide. As Gerd outlined, in people with sickle cell disease, a mutation in hemoglobin causes the red blood cells to take on a characteristic sickle shape. These red blood cells often die prematurely, which causes anemia, and may also damage blood vessels causing vaso-occlusive crises, or VOCs, which appear as episodes of extreme pain as well as stroke, acute chest syndrome and other forms of organ injury. Taken together, these complications significantly impact lifespan, underscoring the tremendous need for treatments that address the root cause of this disease. As we look at the existing and emerging treatment landscape, we see a tremendous opportunity for FTX-6058. Approved therapies show modest benefit and only target certain types and aspects of sickle cell disease. Hydroxyurea is the current standard of care, but not all patients respond, efficacy wanes over time, and there are risks and tolerability issues associated with this drug. Other oral or IV programs in clinical development aim to either increase total hemoglobin or reduce VOCs. Clinical studies have shown that increasing total hemoglobin has limited impact on symptoms. Similarly, drugs that may reduce VOCs have minimal to no impact on anemia. Gene editing approaches, which increase fetal hemoglobin have shown potentially curative results, but come with an extremely challenging treatment burden. We believe that an oral medicine that increases fetal hemoglobin will define a new standard of care. HbF induction is the only mechanism that has been shown to broadly improve outcomes in sickle cell disease. As you see on this slide, individuals with sickle cell have baseline HbF levels that are typically between 5% and 10% of total hemoglobin. Based on what we know from those who have hereditary persistence of fetal hemoglobin, any increase of HbF over that baseline improves outcomes. Increases of two to threefold can have life-changing impact along the spectrum shown on the blue arrow, including reduced mortality, reduced pain crisis events and even a functional cure. Using our FulcrumSeek product engine, we identified EED as a biological target that when inhibited, enables robust HbF induction. We developed 6058, a highly potent oral EED inhibitor with outstanding drug-like properties including a highly selective and clean off-target profile. We have extensively profiled 6058 across numerous preclinical models. In both healthy and sickle cell disease models, we observed a consistent two to threefold induction of HbF. We see this level of induction independent of baseline HbF levels. Importantly, in our preclinical studies, HBG mRNA is highly correlated with HbF protein expression. As seen on the right, mRNA and HbF data from healthy CD34 cells and the Townes Mouse model highlight this consistent two to threefold induction and strong correlation between mRNA and protein. In preclinical studies, FTX-6058 generates levels of HbF induction comparable to those reported with BCL11A gene editing. Specifically, in erythroid cells derived from CD34 cells, 6058 achieves a maximal threefold HbF induction in healthy and sickle cell donors. This is similar to published preclinical data shown on the right-hand side of the slide with CTX001, a BCL11A gene editing approach being studied in an early phase clinical trial. CTX001 has since demonstrated that the robust HbF induction observed preclinically translates clinically. We wanted to take a moment to highlight the robust translatability of HbF induction in the CD34 cell assay to the clinic. The HbF induction observed preclinically in healthy CD34 cells across different mechanisms, strongly correlates to the HbF fold induction observed in clinical trials. A high translatability observed with other mechanisms, along with our healthy volunteer data adds to our confidence that 6058's superior preclinical induction will translate to the clinic. As we announced in this morning's press release, we are excited to share new preclinical data showing that 6058 leads to potent down regulation of BCL11A and MYB, which are both well-known repressors of fetal hemoglobin. These data provide additional validation of the potential of 6058 as an oral HbF inducer. As Gerd highlighted earlier, prior genome-wide association studies have identified BCL11A and MYB as critical fetal hemoglobin repressors. Based on these insights, Fulcrum characterized the effect of 6058 and other relevant HbF inducers on the expression of BCL11A and MYB as well as other validated fetal hemoglobin repressors such as KLF1 and LRF. The heat map on the right side of this slide presents this new mechanistic data. As the legend indicates, red represents log-fold increases, while blue represents decreases in mRNA expression. This new data demonstrates that FTX-6058 potently down regulates both BCL11A and MYB mRNA. This is distinct from the activity of the other HbF induction mechanisms, which show little activity on BCL11A. Moving to the next slide. We see that 6058 induced down regulation of BCL11A corresponds closely with HBG mRNA induction and subsequent induction of fetal hemoglobin. When 6058 reduces BCL11A by 50%, we observe a two to threefold induction of HbF. For context, this data is comparable to gene editing data which demonstrates the threefold increase in fetal hemoglobin with approximately a 60% BCL11A reduction in vitro. Importantly, the consistency of the in vitro data sets linking 6058 to reductions in BCL11A is also observed in vivo. Both Wild-type and Townes mice achieved 50% reduction in BCL11A by days 5 to 7 of FTX-6058 treatment. Notably, in the Townes sickle cell disease mouse, persistent BCL11a reduction with 6058 translates to a two to threefold induction of HBG mRNA. We believe that an oral medicine that can reliably increase HbF levels two to threefold above baseline values would be the preferred treatment option for patients and providers and has the potential to redefine the treatment landscape. As an oral HbF inducer, 6058 has the opportunity to address the root cause of the disease without the substantial treatment burden, risks and barriers that come with gene editing, while also offering significant distribution advantage to meet the needs of a global patient population. I would like to now turn the call over to Chris Morabito to provide an update on our clinical data. Chris?

Thanks, Judy. Let me start with a quick overview of the Phase I design. The trial is evaluating the safety, tolerability and pharmacokinetics as well as pharmacodynamic data to assess target engagement, HBG mRNA levels and F-reticulocytes. We have completed all the SAD, MAD and food effect dose cohorts and the recently added 6-milligram cohort in sickle cell disease patients is ongoing. Each MAD cohort has 8 subjects, 6 on drug and 2 on placebo. We chose to measure HBG mRNA in F-reticulocytes in the Phase I trial because of the time course of erythropoiesis in healthy individuals. The proposed site of action for FTX-6058 is on the hematopoietic stem cells that reside in the bone marrow. As you can see on the slide, these newly exposed cells take about 2 weeks to differentiate into reticulocytes and enter the circulation. This provides a narrow window of time to measure any HBG mRNA changes that may be occurring in the context of a 14-day clinical trial. F-reticulocytes provide the first opportunity to assess that HBG mRNA increases are beginning to translate to HbF protein. In the time frame of this study in healthy volunteers, we would not expect to see measurable differences in protein. FTX-6058 has been well tolerated across all dose cohorts in the trial, including the newly reported 20- and 30-milligram MAD and 60-milligram SAD cohorts with no serious adverse events to date and no discontinuations due to treatment emergent adverse events. All treatment-emergent adverse events deemed at least possibly related to 6058 were mild. These data are consistent with our earlier data, and we continue to be encouraged by FTX-6058's developing safety and tolerability profile. Here, you see that the FTX-6058 pharmacokinetic profiles continue to demonstrate dose proportionality at higher doses. The mean half-life remains approximately 6 to 7 hours. There was no food effect observed, further simplifying the oral dosing regimen. It's worth noting before going through the target engagement, mRNA and F-reticulocyte data that these data are now presented against the updated placebo pool, which includes placebo assigned subjects from all cohorts, including the 20-milligram and 30-milligram cohorts. The previously reported data from 2, 6 and 10-milligram cohorts were shown on a backdrop of placebo data pooled from those cohorts. Presenting the data against pooled placebo across all cohorts allows us to see a clearer picture of changes in PD biomarkers across dose levels. Importantly, as I'll show you in upcoming slides, the key takeaways from the data remain the same. We are seeing robust target engagement, dose-dependent HBG mRNA induction that meet or exceed full changes predicted to be transformative for people with sickle cell disease and increases in F-reticulocytes that indicate mRNA is translating to HbF protein. Moving now to the target engagement data. As you see on the slide, the data demonstrate proof of mechanism and robust target engagement across all cohorts as measured by reduction of histone trimethylation. We see reductions in histone trimethylation levels over baseline of approximately 75% to 95% after 14 days of treatment with incrementally higher levels of target engagement at higher doses. We are particularly excited to share the additional HBG mRNA data. The fold induction we are seeing across all the cohorts continues to give us confidence that FTX-6058 has the potential to provide meaningful and significant health benefits, including a functional cure for people with sickle cell disease. On this figure, we're presenting HBG mRNA increases plotted as fold induction over pooled placebo at day 7, day 14 and a safety follow-up, which happened 7 to 10 days after conclusion of treatment. At day 14, we see dose-dependent increases in HBG mRNA ranging from a mean 1.2-fold induction in the 2-milligram dose cohort up to a mean 6.2 fold induction in the 30-milligram cohort. Of note, the 6, 10, 20 and 30-milligram doses all meet or exceed our goalpost of two to threefold induction. The data indicate that FTX-6058 achieved the maximal rate of HBG mRNA induction at the 20- and 30-milligram doses. At safety follow-up, subjects maintained the HBG mRNA induction observed at day 14. As these data suggest, we don't yet know the maximal fold induction, as we're only dosing for 14 days in healthy volunteers. Moving to the next slide. We show the F-reticulocyte data, which indicate HBG mRNA is beginning to translate to HbF protein production. F-reticulocytes are immature red blood cells that contain some amount of HbF protein. These cells are released from the bone marrow into the peripheral circulation around 14 days and provide an early qualitative measure of HbF synthesis. Here, we are demonstrating a mean 1.7 to 3.9 fold increase in F-reticulocytes at the 6-milligram dose or higher at the time of the safety follow-up visit. While fold increases in F-reticulocytes don't correlate to fold increases in HbF, increases of any magnitude indicate the process of protein production has started. Based on clinical data generated from other HbF inducers, initial protein production is typically observed in the 1- to 3-month time frame in people with sickle cell disease. And we plan to measure HbF in our Phase Ib trial in which patients will be treated for up to 3 months. We are very pleased with the results we are reporting today. In summary, the clinical data from healthy volunteers meets or exceeds the two to threefold induction predicted to provide transformative benefit. Preclinically, we have seen HBG mRNA induction consistently translate to the same fold induction of HbF protein. Given the more rapid turnover of red blood cells in people with sickle cell disease, we believe we may see faster and potentially even greater induction in patients. All of this reinforces our conviction and the potential of FTX-6058 to redefine the treatment landscape for sickle cell disease. In terms of next steps, the Phase Ib study will start at 6 milligrams daily for up to 3 months. 2 additional cohorts may be added to assess other doses. Today's data provide more flexibility as they further reform our ability to dose higher or lower than the initial 6-milligram dose, and we will make additional dose decisions based on the initial patient data and PK/PD modeling. The study is designed to confirm and build on our current results with an aim of demonstrating early proof of concept. The trial will enroll individuals with sickle cell disease ages 18 to 65 who can be either on or off hydroxyurea. The primary endpoints are safety and tolerability as well as PK. Secondary endpoints include percent HbF protein and percent F-cells. Additional exploratory endpoints include target engagement, evidence of VOCs, biomarkers of hemolysis and quality of life measures. We believe that HbF induction is a powerful surrogate for clinical benefit in people with sickle cell disease. And the Phase Ib study will provide the first look at protein production in patients treated with FTX-6058. As you'll see here, when we plot the 3-month treatment period for the Phase Ib study against the process of erythropoiesis, we can expect to see protein production starting after approximately 1 month, with maximal HbF induction expected to occur after approximately 3 months. We have a number of milestones coming up with 6058. We plan to start enrollment in the Phase Ib trial by year-end with initial data expected in the second quarter of 2022. Following the Phase Ib, we would move into a potentially pivotal Phase II/III trial in 2023. In addition, we intend to submit an IND by the end of this year to support the initiation of a clinical trial in additional hemoglobinopathies, including beta-thalassemia. With that, I'll turn the call back to you, Bryan.

Thanks, Chris. We are very happy with the clinical results generated with FTX-6058 across all cohorts. These data continue to exceed our expectations. The opportunity to bring a new oral once-daily therapy to people living with sickle cell disease is a very exciting prospect and one that we believe could redefine the treatment landscape for this severe disease. Operator, you may now open the line for questions.

[Operator Instructions] And your first question comes from Matthew Harrison with Morgan Stanley.

Hello, everyone. This is Kostas on for Matthew. Congrats on the data. Two questions from us. The first one is about target engagement saturation. So at what dose do you think that target engagement saturates at day 14. And do you think it can keep increasing with long-term dosing? Or you think it will be the same with the 14 days based on the clinical data? And then I have a follow-on.

Sure. Thanks, Kostas. Let me turn it over to Chris Morabito, and we can speak to the target engagement saturation.

Yes. Thanks, Kostas. And so as you see from these data, we achieved 75% to 95% reduction in histone trimethylation at all doses tested by day 14. And this is consistent with what we saw preclinically that we saw what we think are maximal levels of histone trimethylation decreases via EED inhibition that leave a residual amount of activity within this mechanism. I think clinically, the more important finding is what we see in terms of HBG mRNA induction. And in 2 weeks, we see induction happening at 6 milligrams. So to answer your question about dosing, it could be that there's a dose lower than 6, it could be 2, it could be 4, in which we achieve clinically relevant levels of target engagement. But clearly, 6 establishes that relevance for us. And in terms of saturation over time, consistent with the data and consistent with what we expect from our preclinical data, we don't anticipate additional levels in target engagement to change beyond what we see here.

Very helpful. And the follow-up, can you talk a little bit about the variability in the baseline mRNA HbF levels? And whether there are any outliers with very high or very low baseline levels?

Sure. So the answer is that there really hasn't been significant variability in baseline levels.

Sorry, what was that? I missed. You said the levels are what?

There is -- there has not been significant variability in baseline levels of HBG mRNA.

And your next question comes from the line of Dae Gon Ha with Stifel.

Let me also add my congrats on the update before the year-end. So couple of questions for Fulcrum and then one for Dr. Blobel if he's still around. First is with regards to F-reticulocyte data. Can you maybe walk us through what may have been, I guess, determined by baseline characteristics of the 10-milligram cohort to see a more robust reaction in the safety follow-up period for that cohort versus the 20 and 30 mg. I understand you mentioned the 1 to 3 month is probably more appropriate to detect F-reticulocyte, but just wanted to get a little bit more color. And then secondly, also for the Fulcrum team, as you contemplate the Phase Ib, I guess we won't see the 6-milligram sickle patient cohort data ourselves, but what are you waiting to see from there? And what exactly are the key signals you're trying to detect there to determine your other 2 doses that are TBD in your slide. And then for Dr. Blobel, if we look at your paper that you mentioned, I think it was a 2003 PNAS paper you put up on your slide. I was curious, you also brought up DNMT1, as well as HDAC1 as part of the mechanisms that could potentially induce HbF. Has anyone done or have you had personal experiences with either HDAC1 or DNMT1 inhibition in your sickle cell patients?

So Dae Gon, thank you for the questions. Why don't we start with the first question, and I'll turn it over to Chris, and we can talk about the F-reticulocyte measure as well as what our expectations will be for protein based on what we've seen from other mechanisms as well as just the erythropoiesis process.

So let me just start by reminding you that the data that we're seeing today across the doses that we've looked at demonstrate what we think is robust increases in F-reticulocytes. As robust as we can expect to see in the course of a 14-day treatment period and a total of 21-day observation period. The magnitude of increase in this case is less relevant than the fact that there is an increase. This gives a qualitative assay at this stage of therapy. And it indicates to us that we are, in fact, translating the mRNA transcript into levels of protein that are at least detectable via immunohistochemistry and flow cytometry. In reality, there are no differences in baseline characteristics among the participants at all the dose levels. But we do see quite a bit of variability in the response here. The good news is that the variability -- regardless of that variability, we do see trends that suggest and show us, in fact, that we are producing that protein. And to us, that is the most relevant finding. And I'll remind you that it is the HBG mRNA that ultimately is predictive of the HbF quantity. And we define that based on what we've been seeing in our preclinical assays, both in vitro and in vivo. And it's that HbF that ultimately is the important clinical endpoint here, not F-retics.

And I would also just add, Dae Gon, from a timing expectation perspective, as we mentioned and we profiled some other mechanisms in today's presentation, we very consistently see initial induction of proteins after about a month or 2 in sickle cell patients and maximal protein induction after about 3 to 5 months. So we feel like that's consistent with the erythropoiesis process and will inform our expectations for the Ib. I'll turn it back to Chris, and we can speak to the dosing selection for the Phase Ib as well as the additional flexibility that we now feel like we have based on the data that we shared today.

Yes. Thanks. So we're really excited to start the Phase Ib study as it will define proof of concept. It will give us information about HbF because we'll be dosing long enough. And your question is specifically about how we're going to use the incoming data to determine subsequent doses. As you know, we're going to start at 6 milligrams given daily for up to 3 months. We think that has the potential to translate into meaningful test to participants in the study because it should increase HbF levels to levels that will impact [indiscernible]. We'll be using the incoming data from that study as well as the incoming data from the SCD amendments in the ongoing Phase I study to inform PK/PD modeling. And that will give us a robust model with which we can interrogate opportunities for additional doses, which may be higher or lower, depending on what we're seeing from the incoming data and potentially what we model based on this PK/PD model.

And why don't I turn it over now to Dr. Blobel to answer the question. As it related to DNMT1 inhibitor is...

Yes. So that's an interesting question. So as of DNMT1, there was actually a report earlier this year, I believe, that suggested there are point mutations in this enzyme that can lead to elevated fetal hemoglobin expression, which is consistent with the study. Actually, it wasn't from our lab. It was from [Indiscernible] in 2013 candidate approach. There hasn't been as much done on DNA methylation inhibitors. People have tried this in the early days. This is like when you guys probably were still in high school. And there wasn't that much to report about, and DNMT1 I don't think is necessarily a good drug target, because if you interfere with maintenance DNA methyltransferases, there may be 2 broad off-target effects. As to your question about HDAC inhibitors, that's a very good one, too. HDACs have been tried early on with various broad spectrum HDAC inhibitors such as butyrate. And butyrate has generally not been doing very well in early clinical use. There were also other studies in Susan Perrin's lab on short-chain fatty acids, which can similarly affect HDACs, and the results have not been all that encouraging. And so the HDACs, I feel has fallen into the background again. Maybe I want to use this opportunity to make one additional point. Polycomb proteins are among the first known truly epigenetic regulator. That means they can actually maintain transcriptional programs over cell division, over multiple generations of the cell cycle. And therefore, they are very attractive targets because you could even disrupt polycomb temporarily and might have prolonged effects downside. So if you ultimately envision pulsating a drug or lowering the dose, the effects actually might be sustained for longer periods of time. That's not true for HDAC inhibitors, because histone acetylation turns over much more rapidly than histone methylation, especially the lysine 27 mark that is maintained by polycomb. So I think in that regard, polycomb proteins are better targets in my mind than HDACs.

Your next question comes from the line of Ted Tenthoff with Piper Sandler.

Congrats on more really impressive data on this. So I want to talk about the Ib study a little bit in duration and get a sense for what you expect you might be able to show for that. Clearly, mRNA is moving faster than protein as expected. Do you think we'd get a protein update by the end of the treatment period, appreciating that the primary will be at 4 weeks, but I think you said you're going to dose out to 90 days? And then secondly, will you be measuring any efficacy markers or endpoints, pardon me, in patients such as attack or things like that, just to kind of get a sense?

Sure. Thanks, and I'll turn it back over to Chris talk to the Phase Ib and what our expectations are.

So we're very excited about the Phase Ib [Indiscernible] before the end of the year. And as we've said, it will start at 6 milligrams. And as you point out, the dosing period is up to 3 months. As you also point out, we've established the study to provide us information via a primary analysis at 4 weeks. And we did that because it is the first chance for us to see what could be the potential for meaningful impacts on HbF and would allow us for the opportunity be more agile in our development and inform early decision-making such as selection of dose for the next cohort. So we do anticipate being able to share in Q2 2022 protein data. We haven't guided as to what type or how much, but we will be able to share some at that update that's upcoming. And in terms of the other efficacy markers, we are, of course, going to be looking for evidence of impact on efficacy. You marked already in our announcement today that we'll be looking specifically for changes in VOCs relative to baseline. And we will be following quality of life. Within all that, we will be looking for evidence of impacts on the disease across the spectrum of the disease, including, importantly, the symptoms from anemia and how they may change even over the course of the 3-month treatment period.

And Ted, we would also add that, obviously, as Dr. Blobel went through and as we've spoken about in the past, with hereditary persistence of fetal hemoglobin, there is tremendous support from genetics that we know we are inducing protein that that will ultimately lead to a benefit to patients. And obviously, we'll learn more from the Phase Ib about exact timing.

And your next question comes from the line of Judah Frommer with Credit Suisse.

Congrats on the update here. Just a quick one on the commentary around moving into a potentially pivotal Phase II after the Phase Ib. We did see a competitor in the space kind of move their primary endpoint from a biomarker focus to a functional end point. So just curious on when you think you'll have conversations with the agency on the potential approvability of HbF induction as an endpoint for that Phase II.

Sure. I'll turn it over to Judy and we can speak to both general timing of interactions and our conviction around HbF as a surrogate.

Yes. So as Bryan just noted, HbF is really a very strong indicator of efficacy and data that Gerd showed and that we showed today really outline that consistent relationship and a reliable relationship between increases in HbF and efficacy measures. We remain committed to that. Recently, the FDA has given guidance that HbF as a surrogate is appropriate. We don't believe that there is additional new data that would change our minds. We can't speak for the regulators, but we don't see any data that would change their minds in terms of the appropriateness of HbF as a regulator. Not speaking too much to what another company is doing, but I think that the change in endpoint is most likely the best way to characterize that particular medication, may be more likely to show VOCs than be able to demonstrate the significant increases in HbF that we would feel appropriate to providing transformative levels of therapy. In terms of our own FDA interactions, as Chris mentioned, we're starting a Ib trial. We haven't provided guidance to exactly when we are going to meet with regulators. But as you can imagine, we want to have a robust discussion that is data-enabled. So as we continue with the Ib trial and we look at the data from those cohorts, we'll take a look at the data and more than likely that will be the substrate for a productive discussion with the FDA around using HbF as a surrogate.

Okay. That's really helpful. And just in terms of timing, kind of, as the incremental PK modeling data comes in for the Phase Ib. Is there a chance you kind of scrap the third cohort and things move quicker? Or do you think you'll certainly investigate kind of 2 additional doses beyond the 6 mg?

Yes. And Chris has indicated that we're starting with a 6-milligram dose, which we feel is sufficient to provide clinical benefit. And then as he's also outlined, we are using PK/PD modeling and quantitative pharmacology to expand our understanding of the exposure efficacy relationships. And so we have planned up to 3 cohorts, and that's what we're guiding towards. But as you state, as we develop the model, depending on how informative that is, we're maintaining that flexibility.

[Operator Instructions] Your next question comes from the line of Tazeen Ahmad with Bank of America.

A couple for me. Just to follow up on your point about using fetal hemoglobin as an endpoint. You are going to still look at VOC. How would you be able to, I guess, think of that or how should we think about what to expect on VOC reduction even though fetal hemoglobin would be the focus? And would there be any divergence in terms of what to expect from VOC reduction vis-a-vis clinical efficacy from your prediction of fetal hemoglobin. And then secondly, I just wanted to follow up on the observation of increase in CPK in the healthy volunteers. I know that you stated it was not related to drug, but I was just curious as to what the reason could be.

Sure. Thanks, Tazeen. Why don't I turn it back over to Chris and we can speak -- first speak to as we think about a potential registrational trial, our understanding from the genetics and the relationships between HbF and VOCs.

Yes. The HbF induction hypothesis in sickle cell disease is very well validated by genetics and by emerging clinical data. And any increase in HbF has the potential to have a profound impact on patients. And what we're seeing from our data suggests that we should be able to achieve maximal levels of HbF induction whatever they may be, but maximal levels within a 3-month time frame. So with that in mind, as soon as we have clinically meaningful increases in HbF, we could have impact across the spectrum of disease. And here, we'd expect to see decreases in hemolysis from less polymerization, less sickling of the RBC, which could impact the vascular pathology, it could impact VOCs. And it could do so, say, after a month, maybe even a little bit longer on therapy. So in the context of a relatively short Phase II trial, we expect to see not only impacts on HbF that would be meaningful and translatable to benefit, but also incorporate data from clinical experience with people living with sickle cell disease. Not only VOCs, but also acute chest, priapism, chronic pain, quality of life, fatigue, all of these very burdensome symptoms and signs of the disease that impact their day-to-day activities. Regarding the safety profile, should I continue on?

Yes. I just wanted to maybe get a sense of like what level of production of VOC would you expect to see? Or is it too early to get a sense for that?

Yes. So why don't I turn it over to Paul Bruno, and we can speak to the literature and what the human genetics tell us about the relationship between HbF and VOCs.

Yes. And Tazeen, this is supported by both clinical data with some of the gene therapy and gene editing assets that have been studied to date, as well as genetic data. We can't give you a definitive HbF level in terms of how that leads to reduction in VOCs, it does operate as a spectrum. One thing that we will highlight is that as you get into ranges of 15% to 20% HbF, you do see significant reductions in things like VOCs, ACS and hospitalization.

Okay. That's helpful. And then just wanted to follow up on the CPK.

Yes, sure. So as you point out, we have one additional unrelated increase in CPK. Both of these cases now have been attributed to extreme physical activity in these individuals at safety follow-up. And both of these cases were picked up incidentally without significant symptoms and without significant impacts. It is a safety follow-up, which is 7 to 10 days after the last treatment. And if you remember, the half-life of this is short enough that this drug should be well cleared within the system by that time point.

We have no other questions in queue at this time. I would now like to turn the conference back over to Bryan Stuart for closing comments.

Thank you, and thank you for everybody for joining us today and your support to Fulcrum. Have a great day.

Ladies and gentlemen, this does conclude today's conference. Thank you for your participation. You may now disconnect your lines.

Thank you, everybody. Goodbye.