Fulcrum Therapeutics Inc (FULC) 2021 Q2 法說會逐字稿

Good morning, and welcome to Fulcrum Therapeutics Conference Call. (Operator Instructions)

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.

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. All 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 are going to focus our call on the 6058 Phase I healthy adult volunteer results. Bryan will begin the call with a corporate overview and key updates from the quarter. Chris Moxham will provide a review of the FTX-6058 preclinical data. Chris Morabito will review the clinical results and next steps for the program, and Bryan will open the call for Q&A.

With that, it's my pleasure to turn the call over to Bryan. Bryan?

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 IIb ReDUX4 trial where we were able to show that losmapimod slowed disease progression and improved function in patients with FSHD, a 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 I trial in 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 F-reticulocytes.

In this trial, we saw an impressive 4.5-fold induction of fetal hemoglobin mRNA. We also saw a 4.2 fold increase in F-reticulocytes, which indicates fetal hemoglobin production, and we achieved maximal target engagement. Building on our extensive preclinical research, these results provide proof of biology and mechanism.

We are 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 threefold HbF induction we observed preclinically. This two to threefold 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 Ib trial 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'll note that both of our development programs came from our FulcrumSeek discovery platform, which is a powerful and differentiated approach to drug target identification and the innovation backbone of our company. This has allowed us to rapidly identify novel high-quality targets that modulate the root cause of genetically defined rare diseases.

By enabling drug discovery at unprecedented scale in disease-relevant settings, FulcrumSeek creates an unparalleled opportunity to efficiently grow our pipeline. We expect the work we are doing with FulcrumSeek will enable us to submit 2 new INDs by the first quarter of 2023. In addition, FulcrumSeek has also enabled our ongoing collaborations with both Acceleron and MyoKardia, which continue to proceed well.

As you can see, we continue to make important progress across our clinical development programs, research collaborations and discovery platform. And with the 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.

Thanks, Bryan. Sickle cell disease is a genetic disorder of the red blood cells caused by mutation in the HBB gene. It is the most common type of inherited hemoglobinopathy 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 that remains in this diverse population.

The therapeutic rationale at 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.

What 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 threefold 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 FulcrumSeek drug discovery platform, we identified EED as a biological target capable of robust HbF induction. EED is a noncatalytic 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, 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 activity displays a highly selective and clean off-target profile. We were also issued a composition of matter patent, which provides protection until 2040.

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 threefold 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 CD34 positive cells and the Townes mouse model that highlight this consistent two to threefold 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 CD34 positive cells, FTX-6058 achieves a maximum threefold HbF induction in healthy and sickle cell donors. This is similar to published data from Vertex and CRISPR Therapeutics demonstrating an approximate threefold HbF induction in CD34 positive cells from healthy donors by CTX001, a BCL11A gene editing approach now being studied in a Phase I/II 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 in response to treatment with FTX-6058. What we observe is the characteristic two to threefold 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 HbF levels two to threefold, 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 to date, 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, an effective oral small molecule HbF inducer, such as FTX-6058, has the potential to be disease modifying, addressing sickle cell disease pathology and symptomatology. Couple this potential for broad therapeutic benefit with the convenience of oral administration and distribution at scale to meet the 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 I healthy volunteer trial, we've included exploratory measures of HBG mRNA and F-reticulocytes. One of the key reasons we're quantifying these is due to 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 site 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 2 weeks to differentiate into reticulocytes 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 developed a highly sensitive and robust droplet digital PCR assay to quantify HBG mRNA.

Also, as reticulocytes 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 utilized an F-reticulocyte measure that relies on specific immunodetection 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 is 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?

Thanks, Chris. I'd like to take a moment to remind everyone that the results we will be sharing are from our ongoing Phase I clinical trial in healthy volunteers. As a reminder, the aim of the ongoing Phase I 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 F-reticulocytes, which are reticulocytes 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 effect 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 SAD cohorts 1 through 6 and MAD cohorts 1 through 3.

FTX-6058 was generally well tolerated in all the SAD and MAD cohorts completed state. 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 1 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 profile demonstrated dose proportionality across the SAD and MAD cohorts. The mean half-life is approximately 6 to 7 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 3 exploratory endpoints measured in our Phase I trial.

Shown on this slide is the target engagement data demonstrating potent and robust inhibition of histone trimethylation, the key epigenetic mark facilitated directly by PRC2. We collected samples at baseline denoted as day minus 1. We then collected samples that measure target engagement at days 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 2 milligrams 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 in HBG mRNA, demonstrating proof of biology. Here, we're presenting these pharmacodynamic effects in data as 3 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 dose proportionality. At 2 milligrams, there is evidence of HBG mRNA induction at days 7 and 14 though not statistically significant. In both the 6 and 10-milligram cohorts, we observed statistically significant HBG mRNA induction with the 10-milligram cohort achieving a mean 4.5-fold induction after 14 days. You can also see we're getting up to a maximum eightfold 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 at safety 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 the HbF protein expression as well. This type of durability is also consistent with what we've demonstrated preclinically in the Townes mouse model.

Before we move on, I want to contextualize this mean 4.5-fold HBG mRNA induction by reminding you that we observed a two to threefold induction of mRNA across multiple models preclinically 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 preclinically HBG mRNA induction was also strongly correlated with HbF protein induction.

Last, we will present the F-reticulocyte clinical results, where we again see evidence of a dose proportional PD effect. To remind you, an F-reticulocyte is a reticulocyte that contains HbF protein. While we did not observe F-reticulocyte increases in the 2-milligram cohort after 14 days on treatment, we observed statistically significant increases at safety follow-up after the 14-day treatment period in both the 6- and 10-milligram cohorts. FTX-6058 treatment in the 10-milligram cohort demonstrated a mean 4.2-fold increase in F-reticulocytes, which indicates that persistent HBG mRNA induction is translating to 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 erythropoiesis in healthy individuals. We observed maximal target engagement by 7 days, HBG mRNA induction by day 14 and F-reticulocytes 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 volunteer setting.

In summary, the results presented today meet the induction thresholds predicted to provide meaningful clinical benefit to sickle cell disease patients. Extensive genetic and clinical literature indicate that a two to threefold induction in HbF protein has the potential to translate to broad clinical benefits. We have also demonstrated preclinically 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 to HbF protein based on the strong correlation between mRNA and protein expression based -- observed preclinically as well as the strong correlation observed between HBG mRNA and F-reticulocytes 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 I trial at a medical conference at the end of the year, pending abstract acceptance. Based on what we reported today, we also intend to enroll sickle cell patients in a clinical trial in the fourth quarter of this year. The multiple dose Phase Ib trial will start with the 6-milligram dose and include a treatment period of up to 3 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 II/III clinical trial that will start in 2023. In addition, the clinical results to date support the initiation of a clinical trial in 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.

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-reticulocytes 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 are very excited about the prospects for our programs in FSHD and sickle cell disease, 2 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 Instructions) Your first question is from the line of Ted Tenthoff from Piper Sandler.

Remarkable results. Is there any -- from the modeling, what would you anticipate to see from 20 mgs? 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? And congrats, it's great data.

Thanks, Ted. I'd turn it over to Chris Morabito and he could speak a little more to the Phase Ib study and what we would anticipate seeing there.

So Ted, thanks for the question. The first question was about 20 milligrams. I assume you mean the ongoing clinical trial, is that correct?

Yes.

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 3 doses. So I don't think we'll exceed that. And 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 we -- I can't predict what that number will be at this point. And then similarly with F-retics, 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 threefold induction, which is what we predicted to us is a very meaningful result, and we look forward to continuing that -- continue with that goalpost in mind as we move forward into the Phase Ib 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 healthies compared to sickle cell patients.

Having said that, in patients, human patients, where the bone marrows more permissive and where RBC half-life is shorter because of the pathology of the disease, it's quite likely that we will see more significant changes, a more full induction or potentially faster induction compared to what we're seeing in healthies. Of course, this is the point of the Ib study that we'll be starting later on this year, and we'll certainly be excited to share those results as they come forward.

Your next question is from the line of Dae Gon Ha from Stifel.

Congrats from me as well. Just to kind of follow up on the next plan or the patient trial, Phase Ib MAD study. Just wondering, given the chronic dosing that's likely from this oral-administered drug, what are your thoughts on, I guess, the treatment magnitude that you can expect? I know you mentioned two to threefold. So should we expect 4 to 4.5 that we saw in 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?

Thanks, Dae Gon. I'd turn it over to Chris Morabito, again, and if he can break that question out into 2 answers. One is just contextualizing the fold increases that we're observing relative to the starting fetal hemoglobin levels that most sickle cell patients have. And then 2, we can comment on what we've observed from a safety tolerability perspective.

Yes. Great. So Dae Gon, thanks. The Phase Ib will be our first chance to see the effects of this drug in patients. We're really excited doing that. And as indicated, in fact, it will be an open-label study, so we'll be able to get feedback relatively continuously as we progress through the study. The goalpost for the study will be two to threefold induction. But as ultimately, as Bryan intimated, setting up his 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 could see potentially profound effects on patients.

Patients with sickle cell disease are with roughly 5% to 10% HbF level and increasing by a magnitude of 2% to 3% would get us to that 10% to 30% range, which is where we would expect to see important clinical changes. We could potentially start to see even in the Phase Ib, but we certainly would expect to observe in the future Phase II/III 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 profile based on the Phase I results to date. There's 2 weeks of doing, as you point out, this is not chronic dosing. But based on these 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 will give us these kinds of results as we're seeing now in healthy volunteers.

If I can just add one more question, just maybe a really dumb question, but recognizing it in healthy volunteers, but the 4 to 4.5-fold increase that you saw, any chance you could put some percentage value that 10% to 30% higher...

Dae Gon, I'm sorry, we're having a tough time hearing you.

Operator?

Yes, ma'am. I'm sorry. Sir, you might have been speaking on your speaker phone. Please pick up your handset, so we can hear you clearly.

Can you guys hear me now?

We can. Thanks.

Great. Yes. 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 or similar exercise in these healthy volunteers now that you've seen the fourfold increase or induction, do we even get the percentage value on the HbF or is that completely out of the question?

Yes. Dae Gon, why don't I turn it over to Chris Moxham. He can speak more to what we've seen preclinically in CD34s both from sickle donors as well as healthy donors.

Sure. So again, what we've observed preclinically is this two to threefold induction above baseline. And in absolute terms, we have certainly seen absolute levels of HbF, as I pointed out, with the 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, 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 had us then pointed towards detecting HbF protein in the context of F-reticulocytes.

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 using HPLC to quantify HbF in absolute terms as it's typically done in a longer duration Phase Ib study.

Your next question is from the line of Joseph Schwartz from SVB Leerink.

Congratulations from me as well. I was wondering if you have any more thoughts on why you saw a greater efficacy in healthy volunteers than the two to threefold 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 or are there any other factors in your view that might have contributed?

Sure. That's a very good question. And we don't have any clear indicators as to why today. I think the notable difference perhaps between the preclinical data, again, where we showed very robust two to threefold increases in HbF, for example, in the Townes mouse model system, which again is humanized in the context of the globin genes, but still is operating under the control of the mouse for the mirroring transcription factors. Now we're in a 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 of 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 threefold induction to provide meaningful clinical benefit and certainly look 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 a shorter half-life in sickle cell setting. So I think that whole context gives us a greater opportunity to see even greater induction.

Okay. That's very interesting. And then I recall that FTX-6058 has been developed to have high pancellularity. I was wondering if you could talk about whether you have been able to evaluate that attribute in healthy volunteers and what the implications are for when you get into patients?

Yes. And Joe, I'll turn it over to Chris, and he can remind you of just what we did observe preclinically and then what we expect here.

Yes. So again, preclinically, what we did observe is a very robust pancellular 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 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 pancellular induction. But certainly, again, based upon the preclinical data, either in healthy cells that were derived from a healthy donor or CD34 cells obtained from a sickle cell donor, we see a very consistent two to threefold induction and a very consistent pancellular induction in either setting.

Okay. Great. And then if I could just ask a bigger picture question. What do you think are the implications of this work on the broader FulcrumSeek platform? Are there 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?

Yes. Thanks, Joe. I'd say broadly, obviously, we're very enthusiastic, both about this data and the FSHD data in terms of being validating for FulcrumSeek and our approach. So both of these programs, as we've talked about, came out of the FulcrumSeek engine: one of them, 6058, we used our own medicinal chemistry and created this compound that we're very excited about; and then the other, in FSHD, we identified a target that had chemical matter that we were able to in license.

So we feel like there's great validation. We're very excited with 6058 to be taking that into other select hemoglobinopathies as we referenced and feel like that really broadens the opportunity. And additionally, I would say hematology, as we think about FulcrumSeek, remains an area of focus and the type of commitment and expertise we're building in the area, we feel like we'll really lend itself to other programs as well.

Your next question is from the line of Matthew Harrison from Morgan Stanley.

I guess a couple of 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 mg 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 in healthy volunteers?

Thanks, Matthew. And I'd turn over to Chris so he could talk about how we're thinking about dosing in the Ib as well as the second question, cumulative change.

Yes. Great. So as I said, the first dose for the upcoming Phase Ib study will be 6 milligrams, and we intend to dose up to 3 months in an open-label way at 6 milligrams. We haven't yet determined the second dose for the study. It could be 10 milligrams based on these data that we reviewed today and maybe 20 milligrams based on the data that will come in from the healthy volunteer study that's still running.

We want to choose 2 doses that will give us dose-ranging information in the Ib study so that we could select 1 dose for the potentially pivotal Phase II studies. So the broad range of doses in the Ib would give us a broad range of PK and PD responses with which we can build a robust model and select that dose. We 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 goalpost here would be the two to threefold increase in sickle cell patients at either of the doses or any of the doses that we test in the Phase Ib study. We, of course, will be thrilled to see increases over that, especially in HbF protein levels. But as I mentioned before, and Chris and Bryan have reiterated, that two to threefold increase would be transformational, particularly when this is given as an oral medicine.

(Operator Instructions) Your next question is from the line of Tazeen Ahmad from Bank of America.

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 you report the results of increases in HbF protein? And then I have a couple of follow-ups.

Yes. So we plan to begin enrollment of the Phase Ib trial in the fourth quarter of this year, and we plan on providing an update in the second quarter of next year.

Okay. 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 to be?

Yes. So as we discussed, as we laid out in the slide where we talked about the process of erythropoiesis, the first time that we would expect to see HbF protein -- quantifiable HbF protein would be in patients around a month. And then after 3 months, we would be much more likely to see that. It just takes longer for the HbF protein to be quantifiable in the periphery. And then...

And are patients -- do patients uniformly respond or is there variability?

Go ahead, Chris.

Yes. To that question, what we've seen preclinically 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 a sickle cell donor or even that donor with sickle cell trait. Now 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 to date, a very robust and significant increase in HbF protein levels after treatment with 6058.

And then last question for me. Based on that, would you expect that the entire SCD population would be eligible? Or would you have certain criteria at least for trial enrollment?

Yes. The entire population is eligible for this, absolutely.

Your last question is from the line of Judah Frommer from Credit Suisse.

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 or any conversations with the agency that may help you move forward on either a biomarker or another perspective?

Yes. I would say in terms of the bar, as you referenced, there's 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 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 onefold 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 Ib trial, be able to select a dose with the hope to then move into a Phase II/III registration trial and the opportunity to potentially bring this to patients as quickly as possible.

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.