Earnings Call Transcript - FULC Q3 2021

Naomi Aoki, Senior Vice President of Corporate Communications and Investor Relations

Thank you, Henry. Good morning and welcome to the Fulcrum Therapeutics conference call. Please be reminded that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our future expectations and plans, clinical development timelines and financial projections. While these forward-looking statements represent our views as of today, they should not be relied upon as representing our views in the future. We may update these statements in the future, but we are not taking on an obligation to do so. Please refer to our most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with our business. With me on today's call are Bryan Stuart, President and Chief Executive Officer; Chris Morabito, Chief Medical Officer; and Peter Thomson, Vice President of Finance & Accounting. Judy Dunn, our President of R&D, and Paul Bruno, our Senior Director of Corporate Development, will also be available for Q&A. Let me run quickly through this morning's agenda. Bryan will begin the call with a corporate overview and key updates. Chris Morabito will review our programs in sickle cell disease and FSHD. Peter will cover our financials and then Bryan will open the call for Q&A. With that, it's my pleasure to turn the call over to Bryan.

Bryan Stuart, President and Chief Executive Officer

Thank you, Naomi. Good morning everyone and thank you for joining us today. 2021 has been a remarkable year for Fulcrum, and we continue to make great strides in the third quarter across our pipeline, our product engine, and our business, bringing us closer to our mission of delivering life-changing medicine to people with rare genetic diseases. This past quarter was particularly notable for the compelling clinical data we reported on FTX-6058, our oral HbF inducer for sickle cell and other hemoglobinopathies. In August, we reported results from our ongoing Phase 1 trial in healthy adult volunteers. As many of you know, the current treatment landscape in sickle cell disease consists of therapies that only target select symptoms. Human genetics clearly demonstrate that by inducing fetal hemoglobin (HbF), we treat the root cause of sickle cell disease, and by inducing HbF we believe FTX-6058 has the potential to address the broad range of symptoms, providing a functional cure with an oral therapy. As you'll hear from Chris Morabito later on, we are excited about the results from this trial, both in terms of the tolerability profile and the robust induction of HbG mRNA, which has been highly correlated in our preclinical studies with HbF induction. Looking ahead, we remain on track to provide an update from our ongoing Phase 1 trial by year-end, including data from our 20 mg and 30 mg dose cohorts in healthy volunteers. At that time, we also plan to share new data further elucidating the relationship between EED inhibition via FTX-6058 and HBG mRNA expression. Meanwhile, we are moving quickly to initiate our Phase 1b trial in people living with sickle cell disease and are on track to begin enrolling patients by the end of the year. We also plan to submit an IND for FTX-6058 by year-end in additional hemoglobinopathies including beta thalassemia. Now let’s turn to losmapimods, our candidate for FSHD. FSHD is the second most prevalent form of muscular dystrophy. There are currently no approved drugs and nothing else in the clinic for this devastating disease. People with FSHD are typically diagnosed in their late teens or early twenties. As fat progressively infiltrates their muscles, people with FSHD lose strength, function, and independence. There is an urgent need for a drug that can slow or stop disease progression. The data we reported earlier this year from our Phase 2b ReDUX4 trial highlights losmapimod's potential to do just that, demonstrating delayed progression and even improvement across a number of measures of muscle health, function, and patient-reported outcomes. We remain on track to meet with regulators before the end of this year and look forward to providing an update on those discussions in the first quarter of 2022. Turning to FulcrumSeek, our product engine and innovation backbone of the company. FTX-6058 and losmapimod, as well as our ongoing collaborations with Acceleron and MyoCardium, are a testament to the power of FulcrumSeek, which has allowed us to rapidly identify novel, high-quality targets that modulate the root cause of genetically defined rare diseases. Notably, in addition to our IND in hemoglobinopathies, we expect to submit an additional IND by the first quarter of 2023. We have also made tremendous advancements with FulcrumSeek to enable our drug discovery efforts and what we believe is an unprecedented scale in disease-relevant settings, positioning us to dramatically increase the pace of discovery. As we shared this morning, Chris Moxham, our Chief Scientific Officer, will be leaving Fulcrum to pursue new opportunities. We are grateful for his contributions and wish him the best in the next chapter of his career. During this transition, the discovery organization will continue to report to Judy Dunn, our President of R&D. With her leadership and strong organization already in place, we're well-positioned to execute against our discovery goals. Finally, we continue to build out our leadership team this quarter with the appointments of Mel Hayes as our Chief Commercial Officer, Mani Sundararajan as our Senior Vice President of Technical Operations, and Naomi Aoki as our Senior Vice President of Corporate Communications and Investor Relations. These newly created roles help us build out our downstream capabilities and further strengthen our team as we move closer towards becoming a commercial organization. Fulcrum is in a tremendous position as we look to build a leading rare disease company. We are advancing two potentially life-changing therapies in clinical development, progressing additional early-stage programs, scaling up our discovery efforts, and building downstream capabilities, all on a strong financial foundation with the cash runway that now takes us into 2024. With that, I’d like to turn the call over to Chris Morabito.

Chris Morabito, Chief Medical Officer

Thanks Bryan. I’ll first start with FTX-6058, our oral HbF inducer. As Bryan mentioned, we're extremely encouraged by the results we’ve reported in August, which suggests that FTX-6058 could be a transformative therapy for people with sickle cell disease. Sickle cell disease affects an estimated 100,000 people in the U.S. and millions more worldwide. In people with sickle cell disease, a mutation in hemoglobin causes red blood cells to take on a characteristic sickle shape. These red blood cells often die prematurely, causing anemia. The sickle cells may also damage blood vessels and restrict blood flow, causing vaso-occlusive crises or VOCs, which appear as episodes of extreme pain and can manifest as strokes, acute chest syndrome, and other forms of organ injury. Together, these complications significantly impact lifespan, underscoring the tremendous need for treatments that address the root cause of the disease. As an oral HbF inducer, FTX-6058 has the potential to redefine the treatment paradigm. The link between HbF induction and improved outcomes in sickle cell disease is very well established, with both genetic and clinical data showing that increased HbF reduces or eliminates anemia, VOCs, and other symptoms of the disease. People who carry the sickle cell mutation and also have persistence of fetal hemoglobin present with much milder disease and have far better clinical outcomes. Typically, people with sickle cell disease have about 5% to 10% HbF, and we know from those with persistence of fetal hemoglobin that any increase in HbF beyond this has a positive impact on clinical outcomes. We believe an oral drug that induces HbF by two to three folds from baseline would be life-changing for people with sickle cell disease, with potential to decrease both anemia and VOC-driven symptoms. Pre-clinically, FTX-6058 has been shown to induce HbF by two to three fold in a wide variety of cell and disease models, and the interim clinical trial results we reported in August show those preclinical data starting to translate clinically. The data demonstrate proof of biology and mechanism as evidenced by dose proportional induction in HbG mRNA up to a mean 4.5 fold increase in the 10-milligram dose cohort. Our preclinical studies consistently demonstrate that increases in HbG mRNA and HbF protein are highly correlated. Based on these results, we are aggressively moving ahead with this program. We have added a cohort of people with sickle cell disease to the ongoing Phase 1 trial. The addition of this cohort helps us make our PK/PD model more robust more quickly and will further inform additional doses in the Phase 1b study. Dosing for this cohort will be 14 days at 6 milligrams once daily. In terms of the next steps for the program, we anticipate sharing results of the 20 mg and 30 mg cohorts of the ongoing Phase 1 trial before the end of the year, as well as data to shed light on the intermediary steps between EED inhibition via FTX-6058 and HBG mRNA expression. As a reminder, the aim of the Phase 1 is to evaluate safety, tolerability, and pharmacokinetics of FTX-6058. The trial has also been collecting pharmacodynamic data to assess target engagement and HBG mRNA levels. Additionally, we are on track to begin enrolling people with sickle cell disease in the Phase 1b clinical trial before the end of this year. This multiple-dose Phase 1b open-label trial will start with the 6 mg dose and include a treatment period of up to three months with about 10 patients per cohort. The study is designed to confirm and build on our current results, with the aim of demonstrating early proof of concept in sickle cell disease. We anticipate providing initial data from the Phase 1b trial in the second quarter of 2022. Following proof of concept in the Phase 1b, we anticipate moving into a potentially pivotal Phase 2/3 clinical trial in 2023. As we look at the existing and emerging treatment landscape for sickle cell disease, we see a tremendous opportunity for FTX-6058. Only HbF induction has been demonstrated to broadly ameliorate symptoms of the disease. Approved therapies show modest benefits and only target certain symptoms. Other oral or IV programs in clinical development aim either to increase total hemoglobin or to reduce VOCs. Clinical studies have shown that increasing total hemoglobin has a limited impact on symptoms. Similarly, drugs that may reduce the rate of VOCs have minimal to no impact on anemia. Gene editing approaches, which share the same therapeutic rationale as FTX-6058, have shown promising results across the broad spectrum of symptoms that come with an extremely challenging treatment burden for patients and families. We believe that an oral, once daily medicine that can reduce or eliminate anemia, VOCs, strokes, and other symptoms, essentially finding a functional cure, will define a new treatment standard for sickle cell disease. We also believe FTX-6058 could be a transformative therapy for other hemoglobinopathies such as beta thalassemia, with clinical results to date supporting initiating a trial in this patient population, and as Bryan mentioned, we intend to submit our IND by the end of this year. Now let’s turn to losmapimod, a potentially life-changing therapy for FSHD. As many of you know, losmapimod targets the DUX4 gene expression, the genetic root cause of FSHD. This gene expression causes muscle fat infiltration, which leads to degeneration and muscle dystrophy, and relentless progressive loss of function. We consistently hear from patients that their number one concern and objective in a new therapeutic is to slow or stop disease progression in order to preserve the function they have. ReDUX4 is the most comprehensive therapeutic trial in FSHD to date, 48 weeks comparing losmapimod 15 mg twice daily to placebo. In ReDUX4, we saw clinically meaningful impact on muscle structure, function, and patient-reported outcomes. On MRI, we showed a slowing of muscle fat infiltration in patients treated with losmapimod compared to placebo, which speaks to preservation of muscle structure. Patients treated with losmapimod also demonstrated improvement in shoulder strength, a key muscle group impacted by the disease. Importantly, we saw preservation of function measured by reachable workspace, and trends towards improved, maintained timed up and go, which is an assessment of lower extremity function. With reachable workspace, losmapimod treatment resulted in improvements from baseline and reachable surface area, and key areas that impact activities of daily living and maintenance of independence, including reaching above the shoulders and behind the back. And finally, 30 participants on the drug reported feeling better compared to participants on placebo at the end of the 48-week treatment period. Losmapimod also has a well-established safety and tolerability profile. Approximately 3,600 patients have been exposed to losmapimod across multiple indications, and the safety profile remains favorable, especially for a severe and progressive disease for which there are no therapies. In terms of next steps, as Bryan mentioned, we plan to talk with regulators before the end of the year, and we will be providing an update on those interactions in the first quarter of 2022. We're currently planning for our Phase 3 trial, which is our base case scenario, making significant insights from ReDUX4 about meaningful and measurable clinical endpoints that show sensitivity to disease progression and drug effect, and we are applying those insights to inform the design of a trial with the aim of expeditiously delivering the first disease-modifying drug for people with FSHD. On behalf of Fulcrum, I want to express our deep appreciation to the sickle cell disease and FSHD communities for their insights, guidance, and support as we work towards our shared goal of developing much-needed therapies for these difficult diseases. With that, I’ll turn it over to Peter.

Peter Thomson, Vice President of Finance & Accounting

Thanks Chris. Following our successful August financing, we ended the third quarter with $240.3 million in cash, cash equivalents, and marketable securities. Based on our current plans and projections, we expect this will support our operations into 2024. Operational revenue for the third quarter of 2021 was $4.9 million compared to $1.8 million of collaboration revenue recognized during the third quarter of 2020. Research and development expenses for the third quarter of 2021 were $17.1 million compared to $15.6 million in the third quarter of 2020. General and administrative expenses for the third quarter of 2021 were $8.6 million as compared to $5.3 million for the third quarter of 2020, and our net loss was $20.7 million for the third quarter of 2021, compared to a net loss of $19 million for the third quarter of 2020. With that, I’ll turn it back to Bryan.

Bryan Stuart, President and Chief Executive Officer

Thanks Peter. As you've heard today, it’s been a tremendous year for Fulcrum so far and we are continuing to build on that momentum. We are very excited about the prospects for our programs in FSHD and sickle cell diseases, two diseases with great unmet need where we have shown very compelling data to date, and we look forward to opportunities ahead to develop therapies to benefit patients with these and other rare genetic diseases. Operator, you may now open the line for questions.

Operator, Operator

Thank you. Your first question comes from Dae Gon Ha of Stiefel. Your line is now open.

Dae Gon Ha, Analyst

Hi! Good morning guys. Thanks for taking my question. I wanted to go back to the teaser for the additional data with regards to EED inhibition and HBG mRNA. Can you maybe talk a little bit about what we can expect there? Is this mostly in vitro or in vivo, and will this cover transcriptomic analyses or proteomic analysis or something else? And I have a follow-up, thank you.

Bryan Stuart, President and Chief Executive Officer

Yeah, thanks Dae Gon for the question. So we haven't shared more detail yet. I think one of the things that we've been doing and that we’ve spoken about is doing work to try to better elucidate that relationship between EED inhibition via FTX-6058 and this HBG mRNA increase that we’ve observed so far clinically, and obviously the protein increases that we've involved pre-clinically. So we anticipate that we'll be able to share that work along with the data update towards the end of the year and we are excited to share more details on that.

Dae Gon Ha, Analyst

Great! Thank you for that. And then the follow-up is regarding your 30 milligram cohort data. I was wondering if you can maybe walk us through kind of the thought process after you saw the 2 mg, 6 mg, and 10 mg, recognizing 20 mg was coming down the pike. What were the driving factors that led you to the 30 mg cohort and what exactly were you trying to divulge from that cohort data? Thanks so much.

Chris Morabito, Chief Medical Officer

Hi Dae Gon, this is Chris. Yeah, so as you imply, we were very pleased with the data that we reported back in August. Through the 10 mg, we demonstrated a profile that looks like it could achieve our target, which is at least a two to three-fold reduction. So we were pleased to see data that implied that we could hit our goal. And based on what we saw, we made some critical decisions about this program, including the initiation of the Phase 1b study and going into beta thalassemia and other hemoglobinopathies. We haven’t seen anything so far that raises concerns about the profile, but we have taken the opportunity in Phase 1 to continue to learn about the profile, which is why we expanded to 20 mg and then eventually to 30 mg. We want to see more about the slope of HBG mRNA induction, to gather data on target engagement, and continue to assess pharmacokinetics and safety and tolerability. So, those data are helpful for us to inform the future development and we're going to use those to build our plan for expeditiously bringing this towards approval.

Dae Gon Ha, Analyst

Perfect! Thanks for taking the questions. I look forward to it.

Operator, Operator

Thank you. Your next question comes from Ted Tenthoff of Piper Sandler. Your line is now open.

Ted Tenthoff, Analyst

Thank you so much for taking the question, and congrats on a really exciting year. Again, appreciating that we're going to get an update at ASH on 6058, I wanted to get a sense of where things stand for losmapimod and what the next steps are. Thanks guys.

Chris Morabito, Chief Medical Officer

Hi Ted! This is Chris again. We've continuously expressed our excitement about the profile of losmapimod and the data coming out of our ReDUX4 trial, which shows impacts on muscle structure, function, and patient-reported benefits. We believe this has the potential to profoundly impact patients with FSHD, and we are working expeditiously to bring this drug forward toward approval. Our base case continues to be that we’ll have a Phase 3 trial, where we will use the insights we've gained from ReDUX4 about meaningful clinical endpoints that show sensitivity to disease progression and drug effect. We are applying those insights to inform the design of the trial, aiming to expeditiously deliver the first disease-modifying drug for people with FSHD. We continue to be on track to meet with the regulators by the end of this year, and as soon as we have information from those meetings, we’ll share that with you. We share the same goal as the community, which is to have a drug that will profoundly and transformatively act on disease progression and are working with the regulators toward that goal.

Bryan Stuart, President and Chief Executive Officer

And maybe Ted, just to jump in on your perspective regarding the data update. We are preparing to provide an update on both higher dose cohorts as well as the elucidation of the mechanism by the end of the year. Based on the timing of our abstract and the timing of our trial, we are going to present that data outside of the scheduled meetings. As we get closer to that, we’ll keep you informed.

Ted Tenthoff, Analyst

That’s helpful, and thanks for that clarification. Just with losmapimod, does it make sense to evaluate partnerships, even potentially overseas while we keep U.S. sites? Thanks.

Bryan Stuart, President and Chief Executive Officer

Yeah, I think, Ted, as Chris mentioned, we are very excited about our interactions with the FDA and moving the program forward. As we spoke about previously, when we entered the Phase 2b trial, we were enthusiastic to observe patient benefits in what was a relatively small trial of only 80 subjects and in a relatively short trial of only 48 weeks. This gives us confidence and enthusiasm to move forward. As we then transition and look at this as a commercial opportunity, we are very focused on the patient population and the unmet need. We know that these are patients that have this genetically defined rare disease, and for the most part, they are identified. It is a worldwide disease, and there is a patient population that is waiting for a therapy. We are fortunate that we are now building our commercial leadership to put us in a position to take advantage of that opportunity. Our focus is to continue to bring it forward and try to get it to patients as quickly as we can.

Ted Tenthoff, Analyst

Awesome guys! Thanks for the update.

Bryan Stuart, President and Chief Executive Officer

Thanks, Ted.

Operator, Operator

Your next question comes from Matthew Harrison of Morgan Stanley. Sir, your line is now open.

Kostas Biliouris, Analyst

Good morning everyone. This is Kostas for Matthew. Thanks for taking our questions and Chris, good luck with the next steps. Two questions from us on sickle cell disease. The first one is, can you talk a little bit about the relationship between the PK and the target engagement that you have seen so far with the available data, and whether the target engagement is Cmax or AUC driven? Secondly, we are wondering whether you are planning to share baseline mRNA levels with us. Thank you.

Bryan Stuart, President and Chief Executive Officer

Hey Kostas, this is Chris. Yeah, thanks for the questions. So referring back to what we showed in August, you recall that we had achieved maximal target engagement at all three doses tested: 2 mg, 6 mg, and 10 mg. It took a little longer for 2 mg to get there. By seven days, 6 mg and 10 mg were about the same at roughly the maximum level, and surely by 14 days, all three dose levels were at maximal level. Maximal inhibition, defined by changes in histone trimethylation, retained about 20% to 30% of PRC2 activity, which we think is an intrinsic competitive advantage of this particular mechanism. So there is something here regarding the concentration and its relationship to target engagement. Our preclinical data suggest that this relationship is based on exposure rather than Cmax. The data we showed back in August also implied that there's a pretty long residence time. It takes about a week or so for the levels of histone trimethylation to return to normal, even though the half-life of the drug is only about 9 hours. So again, it’s an exposure driven relationship that has a durable effect.

Chris Morabito, Chief Medical Officer

And then Kostas, we can address the second question regarding mRNA levels. Yeah, so that’s not something that would be important in healthy individuals. It’s more important in those who have sickle cell disease, and so this is not something that we intend to share. The most important information that we’ll share about mRNA changes is the fold increase from baseline. When we start talking about the patient population, there will be significant levels of HbG and ultimately of HbF where it will be relevant and where we'll have longer treatment durations. This is when we’ll begin to report on the essential parameters.

Bryan Stuart, President and Chief Executive Officer

And Kostas, I think we would also add one of the things that we mentioned and have been very enthusiastic about, is just this consistency we have observed to-date. As Chris mentioned, across both mRNA, and protein pre-clinically. So whether we looked at the Townes mouse model, a wild-type mouse, or CD34 cells from sickle patients or from healthy volunteers, we have seen this very consistent two to three-fold induction of both mRNA and protein. As we looked at our initial Phase 1 healthy volunteer data, where we looked at mRNA, we are very enthusiastic to see this induction that was even beyond that two to three fold. I think all of that gives us confidence as we look to translate into sickle cell patients. The other element that does as well, is just looking at some of these other opportunities, such as the gene editing programs where we have seen meaningful translation from the CD34 positive assay pre-clinically into now what's being observed with BCL-11A gene editing in patients. All of that gives us confidence that as we get into patients here by the end of the year, we have the potential to achieve meaningful results.

Kostas Biliouris, Analyst

Very helpful, thank you.

Operator, Operator

Your next question comes from Joseph Schwartz from SVB Leerink. Your line is now open.

Joseph Schwartz, Analyst

Thanks very much. Congrats on all the progress as well. I was wondering how well developed is the understanding about potential natural variability around the thresholds of HbF that are associated with varying degrees of symptoms in sickle cell, and how are we measuring symptoms in the Phase 1b study in SCD patients? Is it just VOCs, or are there any other finer metrics you’ll be evaluating?

Bryan Stuart, President and Chief Executive Officer

Yeah, so Joe, why don’t I turn it over to Paul Bruno and he can speak to not only what is known from data as well as other clinical trials about starting HbF levels, but also what is very clearly known about induction of HbF and the benefits from human genetics. And as we’ve talked about inducing HbF, it is the only way to be able to treat the root cause of the disease, and we have such a wealth of data from these patients that have hereditary persistence of fetal hemoglobin that we’re really able to build on that.

Paul Bruno, Senior Director of Corporate Development

What Bryan said. Looking across the various clinical trials that are currently ongoing, looking at CRISPR therapeutics and even past trials of hydroxyurea, as well as observational studies in sickle cell disease, we do feel very confident about this baseline level sitting between 5% and 10%. As Bryan alluded to, what we know from the genetics in sickle cell disease and those who have mutations leading to hereditary persistence of fetal hemoglobin is that any increase in fetal hemoglobin results in amelioration of a broad range of symptoms within sickle cell disease. Things like anemia, VOCs, acute chest syndrome, and so on. Chris, you can speak to the Phase 1b expectations.

Chris Morabito, Chief Medical Officer

As Paul mentioned, HbF is a surrogate, and increases in HbF in the setting of sickle cell disease are associated with improvements in anemia, as well as improvements in symptoms from anemia and improvements in things like VOC and VOC-related phenomena. We will be studying this in the Phase 1b study for up to three months, which is the expected duration of having a maximal impact on HbF in patients. We will look into this across significant changes in HbF, and we expect that in a few months period in an open-label study without a placebo group, we won't be able to provide robust data on changes in VOCs, as we don't have a baseline to compare to for a placebo. However, we will be looking for any signs that could impact that. We expect that with longer studies, such as the Phase 2, we will be in a better position to demonstrate significant improvements in clinical outcomes.

Joseph Schwartz, Analyst

Okay, thank you. For your meetings with the FDA for Losmapimod, I was curious how much patient advocates may be able to chime in on the merits and need for the drug. Can you give us any sense of how much bandwidth might be allocated by the FDA to receive the case for approval from the company versus from patient advocates?

Bryan Stuart, President and Chief Executive Officer

Yeah Joe, why don’t I turn it over to Chris to address that. We can also speak to some of the things that have been done from a community perspective to engage with the FDA. The patient-focused drug development that took place in 2020 provided us with valuable insights from the patient community about the need for therapies.

Chris Morabito, Chief Medical Officer

It’s a wonderful question and certainly something we’ve been thinking about deeply. We've now built an internal group focused specifically on patient engagement and patient advocacy. The patient advocacy network in the U.S. and outside, in Europe and the U.K. for example, are strong and very active, and even outside those organizations, patients themselves are very engaged and willing to help us. The patient community is eager to help regulators like the FDA understand the burden of this disease. Bryan referred to a conference that was held in June of 2020, which produced a voice of the patient record, held in conjunction with the FDA through panels of experts including patients who participated in the conference. The top report was that patients requested new therapy that would slow or halt disease progression, something like what we think the profile of losmapimod can achieve. We are actively engaged with these organizations to communicate the burden of disease in FSHD and to help regulators understand what kinds of functional interventions or patient-reported outcomes are important to this community. We are collaborating with the community to identify what assessments we can use in ongoing clinical trials to provide robust evidence to support approvals. The FDA has been engaged, and we are encouraged by this involvement and look forward to continued collaboration with regulators.

Joseph Schwartz, Analyst

Thanks again.

Operator, Operator

Your next question comes from Judah Frommer of Credit Suisse. Your line is now open.

Judah Frommer, Analyst

Hi! Thanks for taking the question and congrats on all the progress. Just a couple of follow-ups on the Phase 1b design. Can you remind us why you decided to dose with the 6 mg dose and not the 10 mg, and how impactful could the Phase 1b readout be to moving into Phase 2 versus the data generated in healthy volunteers given that it is that one dose?

Chris Morabito, Chief Medical Officer

Yes, just to give you the context of the study design, it will be up to three months of therapy in patients with sickle cell disease, and it is all conversation around sickle cell disease. We're looking first at safety and tolerability while also looking for changes in key pharmacodynamic parameters, including HbF. We believe the three-month treatment duration gives us the opportunity to assess this. We anticipate having three dose cohorts, each comprising up to 10 patients. We do have a DMC that will be monitoring the study and providing us information at intervals to support continued development. We decided to start at 6 mg because this is the dose level that achieved the three-fold induction at HBG mRNA in healthy volunteers. This is our target, which is a two to three-fold induction on top of baseline in sickle cell patients. Hence, we hypothesized that this is the dose with potential clinical benefits. We also believe that we will have at least the same amount of HBG induction in patients as we see in healthy volunteers, with potential for higher HBG induction due to the bone marrow and erythropoiesis environment in sickle cell compared to healthy. So, we started with 6 mg to give us room to detach HBG changes and ultimately HbF protein changes in patients, continuously assessing as we dose through 6 mg.

Judah Frommer, Analyst

That's helpful, thanks.

Bryan Stuart, President and Chief Executive Officer

Just to finalize this, the subsequent cohorts will be informed by the incoming data and also by the PK/PD model we're building.

Judah Frommer, Analyst

Okay, that makes a lot of sense. And can you remind us, from a clinical perspective, is higher HbF better or is there a threshold effect once you reach the 2x, 3x, or 4x induction level?

Chris Morabito, Chief Medical Officer

Any increase from baseline has been demonstrated in genetic and clinical experiments to provide benefit. We know from very good population studies that even a small change from baseline has a ten-fold impact overall survival over long periods, and this translates well for prognosis. We know from genetics that levels in the range of 20% can significantly impact symptoms, while levels in the 25% to 35% range start to impact absolute symptomatology and can induce a functional cure. Observations from incoming data in gene editing programs indicate levels near 50% can eliminate the disease without causing adverse events. While we see levels in healthy volunteers indicating we can induce to that range, we have no concerns about potential adverse events thus far.

Judah Frommer, Analyst

Great, thank you.

Operator, Operator

Thank you. This concludes the Q&A session for today. I would like to turn the call over to our CEO, Bryan Stewart for closing remarks.

Bryan Stuart, President and Chief Executive Officer

Thank you. Thank you everybody for joining us today, and we appreciate your support of Fulcrum. Have a great day!